Cardiovascular physiology Flashcards

Question

Fig 1.6: The profile of blood pressure and velocity in the systemic circulation of a resting man. The abscissa represents distance along the vessels. Velocity at any level is the ............ divided by the total................ of the vascular bed at that point.

Answer 1

Velocity at any level is the cardiac output divided by the total cross-sectional area of the vascular bed at that point.

Answer 2

Under these conditions: flow (Q) is directly proportional to the pressure difference between the inlet (P1) and outlet (P2) of the tube. Q = P1-P2 By inserting a proporitonality factor (K) into the expression we can change it into an equation describing flow Q = K (P1-P2) Where K is called the hydraulic conductance of the tube. Conductance is the reciprocal of resistance (R) , so we can also write: Q = (P1-P2)/R (Q med dot över) This expression is a form of Darcy's law of flow and is analogous to Ohm's lax for an electrical current. (I = delta V/R) (se 1.4 s 16) It states that flow is proportional to driving pressure (P1-P2) and is inversely proportional to they hydraulic resistance.

Answer 3

Flow is often represent by Q because Q stands for quantity of fluid and the dot denotes rate of passage, this being Newton's original calculus notation.

Answer 4

It should be noted that flow is by definition a rate (the passage of a volume or mass per unit time) and the common expression "rate of flow" is really rather muddling and best avoided.

Answer 5

The total resistance of the systemic circulation in man is around 0.02 mmHg per ml/min, while that of the pulmonary circulation is only 0.003 mmHg per ml/min, and the latter low value explains why a very low pressure suffices to drive the cardiac output through the lungs.

Answer 6

Either the driving pressure must be changed or else the vascular resistance. In normal subjects blood pressure is in fact kept roughly constant, and it is changes in vascular resistance that regulate local blood flow.

Answer 7

During salivation, for ex, blood flow to the salivary glands can increase 10 times due to a fall in vascular resistance to 1/10 its former value, while the driving pressure (arterial pressure) does not increase at all. Changes in vascular resistance are brought about by contraction or relaxation of the vessels, so we should next consider their structure.

Answer 8

The aorta and pulmonary artery divide into smaller arteries, which branch progressively to form narrow high resistance vessel called arterioles. Fig 1.8. Arterioles branch into innumerable capillaries, which ten converge to form venues and veins. The characteristic dimensions of these various vessels are set out in Table 1.2 (human vessels)

Answer 9

Structure of the blood vessel wall: With the exception of the capillaries, all blood vessels have the same basic three-layered plan consisting of a tunica intima (innermost layer), tunica media (middle layer) and tunica adventitia (outer layer) Fig 1.7

Answer 10

Flat endothelial cells resting on a thin layer of connective tissue. The endothelial layer is the main barrier to plasma proteins and also secretes many vasoactive product, but it is mechanically weak.

Answer 11

It consists of spindle-shaped smooth muscle cells arranged circularly and embedded in a matrix of elastin and collagen fibers.

Answer 12

Internal and external elastic laminae (sheets) mark the boundaries of the media.

Answer 13

The tunica adventitia (outer layer) is a connective tissue sheath with no distinct outer border which holds the vessel loosely in place.

Answer 14

The tunica adventitia of the larger arteries contains small blood vessels, the vasa vasorum (literally "vessels of vessels"), and in the largest arteries they penetrate into the outer 2/3 of the media too. Their task is to nourish the thick media of large vessels.

Answer 15

``` Elastic arteries Muscular arteries Resistance vessels Exchange vessels The arteriovenous anastomosis Capacitance vessels ```

Answer 16

Elastic arteris: (diameter 1-2 cm in man). The pulmonary artery, aorta, and major branches, like the iliac arteries, have very distensible walls because their tunica media is particularly rich in elastin, a protein which is six times more extensible than rubber.(see Table 1.3). This enables the major arteries to expand and receive the stroke volume during ventricular ejection and to recoil during diastole, thereby converting the intermittent ejection of blood by the heart into a continuous flow through the more distal vessels. Another protein, collagen, forms a meshwork of strong fibrils in the media. Collagen is 100 times stiffer than elastin and its role seems to be to prevent overdistension.

Answer 17

Diameter 0.1-1 cm in man. In medium to small arteries like the popliteal, radial, cerebral and coronary arteris, the tunica media is thicker relative to the lumen diameter, and it contains more smooth muscle. See fig. 1.8. Tabl 1.3.

Answer 18

The muscular arteries act as low-resistance conduits, and their thick walls help prevent collapse at sharp bends like the knee joint. They have a rich autonomic nerve supply, and can contract but they are not in general important in the regulation of blood flow because their resistance is low. Patients bleeding due to acute trauma: Profound contraction of the media prevent patients to bleed to death. Contraction of muscular arteries can also occur physiologically in cerebral arteries, and the limbs of diving animals.

Answer 19

The arterioles have the thickest wall of all vessels relative to their lumen, the ratio of wall thickness to lumen diameter being approximately 1.0. Fig 1.8.

Answer 20

The muscular walls of the larger arterioles are richly innervated by vasoconstrictor nerve fibres but the terminal arterioles or met arterioles (diameter 10-40 um) are poorly innervated and possess only 1-3 layers of smooth muscle cells.

Answer 21

``` Because of their narrow lumen and limited numbers (Table 1.2) the arterioles form the chief resistance to blood flow in the systemic circulation: The press profile in Fig 1.6 confirms this since the pressure drop across the systemic arterioles is much bigger than across any other class of vessel. ```

Answer 22

When they dilate (vasodilation) the resistance to flow falls and blood flow increases, while vasoconstriction has the reverse effect. Arterioles may thus be regarded as the taps of the circulation, turning local blood flow up or down under the guidance of neural and chemical signals.

Answer 23

The terminal arteriole has one further role; by contracting hard it can prevent blood from flowing through the group of capillaries which arise from it, and can thus regulate the number of functioning capillaries in the tissue. (This job used to be attributed to pre capillary sphincters but it now seems that discrete sphincters only occur in a few tissues, such as the mesentery.

Answer 24

The capillaries are tiny (diameter 4-7 um) and short (250-750 um) and they are so numerous that most cells are no further than 10-20 um from the nearest capillary. The capillary wall is reduced to a single layer of endothelial cells, and the thinness of this layer, approximately 0.5 um, facilitates the rapid passage of metabolites between blood and tissue.

Answer 25

Some exchange also takes place further downstream across slightly larger vessels called post capillary or pericytic venues (diameter 15-50 um), which are microscopic venues lacking the complete smooth muscle coat of larger venues. Some gas exchange also occurs across the walls of small arterioles before blood even reaches capillaries, so the functional category of "exchange vessel" actually embraces both sides of the true capillary network

Answer 26

Although capillaries are extremely narrow, the capillary bed as a whole offers only a moderate resistance to flow. This is partly because of a special kind of flow (chapter 7) and partly because the total cross-sectional area of the capillary bed is very large (Fig 1.6, Table 1.2).

Answer 27

The large cross-sectional area of the capillary bed has the added advantage of slowing the velocity of the blood down to 0.5-1 mm/s, rather as a river slows down when its channel broadens. This slowing allows the red cell a period of 1-2 s in the capillary, time enough for it to unload its oxygen and take up carbon dioxide.

Answer 28

The arteriovenous anastomosis: In a few tissues, notably the skin and nasal mucosa, there are shunt vessels (diameter 20-135 um) which pass directly from arterioles to venues and bypass the capillary bed. Their thick muscular walls are innervated by sympathetic nerves and in human skin they help in temperature regulation. (chapter 12)

Answer 29

Venules (diameter 50-200 um) and veins differ principally in size and number rather than wall structure. They have thin walls which are easily distended or collapsed, and as a result their blood content can vary enormously.

Answer 30

The wall of venues comprises an intima, a thin media composed of collagen and smooth muscle, and an adventitia.

Answer 31

In limb veins the intima possesses pairs of semilunar valves that prevent any back flow of venous blood; but the large central veins and veins of the head and neck lack functional valves.

Answer 32

Venules and small veins are more numerous than arterioles and arteries. (Table 1.2) so they offer a low resistance to flow and a pressure difference of just 10-15 mmHg suffices to derive the cardiac output from venule to vena cava.

Answer 33

The main function of the venous system, besides returning blood to the heart, is to act as a variable reservoir of blood holding about 2/3 of the circulating blood volume---their capacitance function Much of this capacity is located in the numerous venues and small veins of diameter 20 um to 4 mm.

Answer 34

Moreover, many veins are innervated by vasoconstrictor nerve fibers, so their volume can be actively controlled; at times of physiological stress they constrict and displace blood into the heart and arterial system.

Answer 35

The systemic circulation is made up of numerous specialized circuits supplying the brain, kidneys, gut, etc. Usually the blood supply to an organ arises directly from the aorta so that each organ is supplied at full pressure, without any interference by other organs. (see Fig 1.4) This form of plumbing is called "in parallel".

Answer 36

A few organs are connected "in series" with another organ ---that is to say they obtain their blood "second-hand" from the venous outflow of another organ, an arrangement called a portal system.

Answer 37

The biggest portal system is that supplying the liver, which receives approximately 72% of its blood from the intestine and spleen via the portal vein. Fig 1.4. (The portal vein enters the liver at the "porta hepatic" or gateway of the liver; and this is how the term "portal system" arose)

Answer 38

The liver also receives a direct arterial supply via the hepatic artery, so its circuitry is partly in series and partly in parallel. Portal systems have the advantage of transporting a valuable commodity directly from one site to another (e.g. product of digestion from the intestine to the liver) without any dilution of the material in the general circulation.

Answer 39

Portal systems also exist in the kidney where effluent blood from the glomerulus supplies the tubules, and in the brain where a portal system carries hormones from the hypothalamus to the anterior pituitary gland.

Answer 40

A portal system has one serious weakness, however; the down/stream tissue receives partially deoxygenated blood under a reduced pressure head, and as a result the downstream tissue is very vulnerable to damage during episodes of hypotension (low arterial pressure). Renal tubular damage in particular is a not uncommon complication of severe hypotension.

Answer 41

The behavior of the heart and blood vessels has to be regulated in order to deal with varying environmental and internal stresses. This involves nervous and neuroendocrine reflexes, which are coordinated by the brainstem and higher regions of the brain.

Answer 42

The arterial baroreceptor reflex

Answer 43

Baroreceptors in the walls of major arteries sense changes in blood pressure, and reflexly alter the activity of autonomic nerves controlling the heart and blood vessels. This produces changes in cardiac output, peripheral resistance and venous capacitance, and these responses help to restore arterial blood pressure to normal.

Answer 44

The mature heart is built upon a collagenous skeleton in the shape of a fibrotendinous ring (the annulus fibrosus), which is located at the arterioventricular junction.

Answer 45

The atria and ventricles contract in sequence, resulting in a cycle of pressure and volume changes, and a thorough knowledge of the cycle is needed for the diagnosis of valvular defects.

Answer 46

The volume of blood in a ventricle at the end of the filling phase is called the end-diastolic volume and is typically around 120 ml in an adult human. With the closure of the aortic and pulmonary valves, each ventricle once again becomes a closed chamber.

Answer 47

The muscular atria and ventricles are attached to either side of this ring, and the ring is perforated by 4 apertures; each containing a valve.

Answer 48

As well as functioning as the mechanical base of the heart, the fibroendinous ring insulates the ventricles electronically from the atria.

Answer 49

The apex of the heart is formed by the LV and there anterior surface is formed by the RV and RA. The inferior surface of the heart and the pericardium rest on the central tendon of the diaphragm.

Answer 50

The RA is a thin-walled muscular chamber which receives the venous return from the vena cavae and the coronary sinus (the main vein draining heart muscle) Fig 2.2a

Answer 51

The wall near the entrance of the superior vena cava also contains the cardiac pacemaker, the "sparking plug" that initiates each heart beat.

Answer 52

The right atrium communicates with the right ventricle through the tricuspid valve which as it name implies has three cusps, although it is sometimes difficult to distinguish all three. OBS: speciesskillnad

Answer 53

It is the large anterior cusp which is mainly responsible for valve closure.

Answer 54

Each cups is a flexible flap of connective tissue, roughly 0.1 mm thick, covered by endothelium. The free margin of the cusp is tethered by tendinous strings, called chordae tendinea, to an inward projection of the ventricle wall, the papillary muscle. The papillary muscle contracts and tenses the chordae tendinea during systole and this helps prevent the valve from inverting into the atrium during systole.

Answer 55

The anterior wall of the right ventricle is about 0.5 cm thick in man, and resembles a pocket tacked around the septum. Fig 2.2b Expulsion of blood is produced chiefly by the free anterior wall approaching the septum, rather like an old-fashioned bellows.

Answer 56

The outlet from the ventricle into the pulmonary artery is guarded by the pulmonary valve, which, like the aortic valve, consists of 3 equal sized, baggy cusps.

Answer 57

The left atrium receives blood from the pulmonary veins and transmits it into the left ventricle through a bicuspid valve. The large anterior and small posterior cusps are thought to look like a bishop's mitre, hence the name "mitral valve". The cusp margins are attached by chordae tendinae to 2 papillary muscles in the left ventricle.

Answer 58

The chamber of the left ventricle is conical and ejection of blood is produced by a reduction in both diameter and length.

Answer 59

The wall is around three times thicker than that of the right ventricle because it has to generate higher pressures.

Answer 60

the innermost (endocarp-dial) muscle fibres are oriented longitudinally, running from the base of the heart (the fibrotendinous ring) to the apex (tip of the left ventricle); the central fibres run circumferentially; the outermost or epicardial fibre again run longitudinally; and intermediate fibres run obliquely. Fig 2.2c

Answer 61

The muslce orientation changes progressively across the wall. When the chamber contracts, it twists forwards and the apex taps agains the chest wall, producing the apex beat. (This can be felt in the fifth, left intercostal space, about 10 cm from the midline)

Answer 62

The root of the aorta contains a three-cusp valve similar to the pulmonary valve.

Answer 63

The heart is enclosed in a fibrous sac or pericardium, which is lined by a layer of mesothelium and is lubricated by pericardial fluid.

Answer 64

The lower surface of the pericardium is fused to the diaphragm, and as the diaphragm descends during inspiration, it pulls the heart into a more vertical orientation.

Answer 65

The cardiac cycle has 4 phases, and we will begin, arbitrarily, at a moment when both the atria and ventricles are in diastole (relaxed). The timings below refer to a human cycle of 0.9 s duration (67 beats/min), and the data have been acquired by a combination of echocardiography, cardiac categorization, electrocardiogrpahy, and cardiometry.

Answer 66

Ventricular diastole lasts for nearly 2/3 of the cycle at rest, providing ample time for refilling the chamber.

Answer 67

Initially the atria too are in diastole and blood flows passively from the great veins through the open atrioventricular valves into the ventricles.

Answer 68

There is an initial phase of rapid filling, lasting about 0,15 s (Fig 2,3), which has a curious feature; even though ventricular volume is increasing, ventricular pressure is falling. Fig 2.4, also Fig 6.10

Answer 69

The ventricular wall is recoiling elastically from the deformation of systole, and is in effect sucking blood into the chamber. As the ventricle reaches its natural volume, filling slows down, and further filling required distension of the ventricle by the pressure of the venous blood; ventricular pressure now begins to rise.

Answer 70

In the final third of the filling phase, the atria contract and force some additional blood into the ventricle.

Answer 71

In the final third of the filling phase, the atria contract and force some additional blood into the ventricle. In the resting subjects, this atrial boost is quite small and enhances ventricular filling by only 15-20%: indeed, the absence of an atrial boost in patients suffering from atrial fibrillation (ineffective atrail contractions, makes little difference to resting cardiac output. During exercise, however, when heart rate is high the time available for passive ventricular filling is curtailed, and the atrial boost becomes important.

Answer 72

End-diastolic volume, EDV (typically around 120 ml in an adult human) The corresponding end-diastolic pressure (EDP) is a few mmHg.

Answer 73

The reason being that the left ventricle is thicker and therefore less easily distended.

Answer 74

As atrial systole begins to wane, ventricular systole commences. It last 0.35 s and is divided into a brief isovolumetric phase and a longer ejection phase.

Answer 75

As soon as ventricular pressure rises fractionally above atrial pressure, the atrioventricular valves are forced shut by the reversed pressure gradient.

Answer 76

because the cusps are already approximated by vortices behind them in the late filling phase

Answer 77

The ventricle is now a closed chamber, and the growing wall tension causes a steep rise in the pressure of the trapped blood: indeed the maximum rate of rise of pressure (dP/dt) max, is frequently used as an index of cardiac contractility.

Answer 78

Ejection: Duration 0.3 s Inlet valves: closed Outlet valves: open

Answer 79

When ventricular pressure exceeds arterial pressure, the outflow valves are forced open and ejection begins.

Answer 80

3/4 of the stroke volume are ejected in the first half of the ejection phase (phase of rapid ejection, approximately 0.15 s), and at first blood is ejected faster than it can escape out of the arterial tree. As a result, much of it has to be accommodated by distension of the large elastic arteries, and this drives arterial pressure up to its maximum or systolic level.

Answer 81

Vortices behind the cusps of the open aortic valve prevent the cusps from blocking the adjacent opening of the coronary arteries.

Answer 82

As systole weakens and the rate of ejection slow down, the rate at which blood flows away through the arterial system begins to exceed the ejection rate and pressure begins to fall. Active ventricular contraction actually ceases about 2/3 of the way through the ejection phase, but a slow outflow continues for a while owing to the momentum of the blood.

Answer 83

As the ventricle begins to relax, ventricular pressure falls below arterial pressure by 2 to 3 mmHg, but the outward momentum of the blood prevents immediate valve closure. The reversed pressure gradient, however, progressively decelerates the outflow, as shown in the lower trace of Fig 2.4, until finally a brief back flow (comprising less than 5 % of stroke volume) closes the outflow valve (see fig 2.4)

Answer 84

Valve closure creates a brief pressure rise in the arterial pressure trace called the dicrotic wave. For the rest of the cycle, arterial pressure gradually decline as blood runs to the periphery.

Answer 85

It must be emphasized that the ventricle does not empty completely; the average ejection fraction in man is 0.67, corresponding to a stroke volume of 70-80 ml in adults. The residual end-systolic volume of about 50 ml acts as a reserve which can be utilized to increase stroke volume in exercise.

Answer 86

Isovolumetric relaxation: Duration 0.08 s Inlet valves: closed Outlet valves: closed:

Answer 87

With closure of the aortic and pulmonary valves, each ventricle once again becomes a closed chamber. Ventricular pressure falls very rapidly owing to the mechanical recoil of collagen fibres within the myocardium, which were tensed and deformed by the contracting myocytes.

Answer 88

When ventricular pressure has fallen just below atrial pressure, the atrioventricular valves open and blood floods in from the atria. The atria have been refilling during ventricular systole, and this leads us to consider next the atrial cycle.

Answer 89

The cycle of events in the atria produces a cycle of pressure changes in the veins of the thorax and neck (jugular veins) because the veins are in open communication with the atria.

Answer 90

A direct record of pressure in an atrium or jugular vein reveals that there are 2 main pressure waves per cycle, called the A and V waves, and a third smaller wave, the C wave. (see dashed line in Figure 2.4)

Answer 91

The A wave is an increase in pressure caused by atrial systole, and the A stand for atrial.

Answer 92

Atrial systole produces a slight reflux of blood through the valveless venous entrances; this briefly reverses the flow in the venue cavae and raises central venous press to its maximum point (3-5 mmHg).

Answer 93

The next event, the C wave, occurs earlier in the RA than in the neck. In the atrium, it is caused by the tricuspid valve bulging back into the atrium as it closes. In there internal jugular vein, the C wave is caused partly by expansion of the carotid artery, which lies alongside the vein and presses on it during systole: C stands for carotid.

Answer 94

After the C wave, there comes a sharp fall in pressure; called the X descent, which is caused by atrial relaxation, and venous inflow reaches its peak velocity during this phase. See fig 7.20, chapter 7

Answer 95

As the atria fill, atrial pressure begins to rise again, producing the V wave, the V refers to the simultaneously occurring ventricular systole.

Answer 96

Finally, the atrioventricular valves open and the atria empty passively into the ventricles, producing the sharp Y descent.

Answer 97

The cycle of atrial pressure is mirrored in the internal and external jugular veins of the neck, because the latter are in open communication with the superior vena cava. The pulsating jugular veins are readily visible in a recumbent lean subject and this enables the physician to assess the central venous pressure cycle by simple inspection.

Answer 98

What the eye particularly notices in the ned are 2 sudden collapses of the vein, corresponding to the X and Y descents. Examination of the jugular pulse is a regular clinical procedure because certain diseases produce characteristic abnormalities in the pulse. Tricuspid incompetence, for example, can produce exaggerated V waves, because blood leaks back through the incompetent valve during ventricular systole.

Answer 99

0.33 s The various phases do not, however, all shorten to an equal degree (see Fig 2.5).

Answer 100

Ventricular systole does shorten, but only to about 0.2 s, and this leaves a mere 0.13 s for refilling during diastole. Passive filling remains important, but atrial systole contributes relatively more than at rest. Even with the help of atrial systole, 0.12 s is about the minimum interval that allows an adequate refilling of the human ventricle.

Answer 101

Further increase in heart rate, such as the pathological tachycardia which occurs in the Wolf-Parkinson ----White syndrome (> 250 beats/min), actually causes cardiac output to decline rather than increase, because refilling during diastole becomes inadequate. Diastolic interval is thus the chief factor limiting the maximum useful heart rate.

Answer 102

The cardiac cycle is assessed in routine clinical practice by examining various physical signs, such as the arterial pulse, the jugular venous pulse, the apex beat, and the heart sounds.

Answer 103

When a heart valve closes, the cusps balloon back as they suddenly check the momentum of refluxing blood. The sudden tension in the cusps sets up a brief vibration, rather as a sail slaps audibly when suddenly filled by a gust of wind. The vibration is transmitted through the walls of the heart and arteries to the chest wall, where it can be heard through a stethoscope. Provided that the valve is normal, it is only closure that is audible; as with a well-oiled door, opening is silent.

Answer 104

Lubb-dubb should not be taken too seriously, for it appears that only English-speaking hearts go lubb-dubb, while German ones of doop-teup and Turkish ones rrupp-ta.

Answer 105

Precordium Fig 2.3

Answer 106

The first heart sound, a vibration of roughly 100 cycles/s (100 Hertz), is caused by closure of the tricuspid and mitral valves, which close virtually simultaneously.

Answer 107

The second sound is sometimes audibly "split", with an initial aortic component and a fractionally delayed pulmonary component; the sounds might then be represented as lubb-terrupp.

Answer 108

Splitting of the second sound is common in healthy young people during inspiration, because inspiration increases the filling of the right ventricle; this raises its stroke volume, which in turn prolongs the right ventricular ejection time and slightly delays pulmonary valve closure.

Answer 109

2 additional sounds besides the first and second sounds can be detected by phonocardiography, but they are of low frequency and difficult for untrained ears to detect.

Answer 110

The third heart sound is common in young people and is caused by the rush of blood into the relaxing ventricles during early diastole.

Answer 111

The fourth sound occurs just before the first sound, and is caused by atrial systole.

Answer 112

Anatomically, the 4 heart valves lie very close together under the sternum (humans), but fortunately each valve is best heard over a distinct auscultation area, some distance away, because the vibration from each valve propagates through the chamber fed by the valve.

Answer 113

There are 2 fundamental classes of valvular abnormality, stenosis, and incompetence.

Answer 114

There are 2 fundamental classes of valvular abnormality, stenosis, and incompetence: In either case blood passes through the valve in a turbulent jet, setting up a high-frequency vibration which is heard as a murmur.

Answer 115

Benign murmurs in the young: Caused by turbulence in the ventricular outflow tract. This "benign" systolic murmur is caused by turbulence in the ventricular outflow tract. This benign systolic murmur is especially marked during pregnancy, strenuous exercise and anemia.

Answer 116

atrial contraction

Answer 117

The onset of ventricular contraction and the first heart sound.

Answer 118

A beam of ultrasound is directed across the heart from a precordial ultrasonic emitter ( a piezoelectrical crystal), and reflections of the sound from the walls and valves are collected and used to built up a linear record of their motion.

Answer 119

A catheter is treaded through the antecubital vein and advanced under X-ray guidance through the right atrium into the RV, or even into the pulmonary artery.

Answer 120

Femoral artery

Answer 121

Cine-angiography Radionuclide angiography Intracardiac pressure measurement Intracardiac pacing

Answer 122

A radio-opaque contrast medium is injected through the catheter and the progress of the medium through the cardiac chambers is followed by X-ray cinematography (cardiac angiography). This displays the movement of the heart wall and reveals any valvular regurgitation.

Answer 123

A recent extention of the angiographic method is to inject a gamma-ray emitting isotope into a central vein and record the gamma emission with a scintillation camera placed over the precordium. Not only can images of the heart in diastole and systole be computed but also, from the fall in counts produced by each ejection, the ventricular ejection fraction can be measured.

Answer 124

Chamber pressures can be recorded by connecting the catheter to an external pressure transducer, or by mounting a miniature transducer in the tip of the catheter. The pressure drop across a closed valve serves as an excellent test of its competence. A pulmonary artery catheter can also be wedged in the pulmonary arterioles, and the recorded "wedge pressure" is often used as an estimate of pulmonary capillary pressure.

Answer 125

This is a therapeutic application of the cardiac catheter, in which a wire catheter is wedged in the ventricle and used to simulate each heart beat from an external electrical device, thereby replacing the heart's own pacemaker.

Answer 126

The contraction of the myocyte is caused by the shortening of its sarcomeres.

Answer 127

Cardiac muscle is almost incapable of anaerobic phosphorylation, unlike skeletal muscle.

Answer 128

The potential difference between the interior and exterior of a myocyte can be measured by driving a fine microelectrode into the cell.

Answer 129

The resting membrane potential approximates to K+ equilibrium potential, modified by a slight inward background current of Na+

Answer 130

Autonomic nerves adjust heart rate by altering the rate of rise of the pacemaker potential and, in the case of parasympathetic fibers, by increasing the resting membrane potential.

Answer 131

By a special electrical system in the walls of the heart, and this system is constructed of modified muscle cells.

Answer 132

The majority of work cells whose task is contraction, while a minority are specialized cells making up an electrical system whose task is to excite the work cells.

Answer 133

1) a group of cells forming the sino-atrial node or "pacemaker" which discharges spontaneously at regular intervals. 2) Elongated cells called conduction fibres that transmit the resulting electrical impulse quickly to the ventricular work cells.

Answer 134

When the electrical stimulus reaches the ordinary work cell, the latter is excited and fires off an action potential. This leads to a rise in calcium ion concentration within the cell, which in turn activated the contractile proteins of the cell.

Answer 135

The human work cell is typically 10-20 um in diameter and 50-100 um long, with a single central nucleus. The cell is branched and is attached to adjacent cells in an end-to-end fashion. Fig 3.1

Answer 136

The end-to-end junction, or intercalated disc, has a characteristic stepped profile in cross-section, and it contains 2 kinds of smaller specialized junctions; namely desmosomes and gap junctions. As a result of these electrical connections the myocardium acts as an electrically continuous sheet and this enables excitation to reach every cell.

Answer 137

Hold the adjacent cells together, probably by means of a proteoglycan glue located in the 25 nm-wide gap between the cell membranes.

Answer 138

Is a region of very close apposition of the adjacent cell membranes and is thought to be the electrically conductive region through which ionic currents flow from cell to cell.

Answer 139

Because of their resemblance to the myofibrils of skeletal muscle, or myofibrils for brevity.

Answer 140

Each myofibril is composed of smaller units called sarcomeres; which are joined end to end; they are also aligned across the cell, giving the myocyte its characteristic striated appearance under the microscope.

Answer 141

The sarcomere is the basic contractile unit and is defined as the material between two Z lines: a Z line is a thin dark-staining partition composed of a protein, alpha-actinin.

Answer 142

The saromere is 2.0-2.2 um long in resting myocytes and contains 2 kinds of interdigitating filament: a thick filament made of the protein myosin, and a thin filament composed chiefly of actin, another protein.

Answer 143

The thick filaments, of diameter 11 nm and length 1.6 um, lie in parallel in a central region of the sarcomere called the A band. (the A stands for anisotropic, a reference to its appearance through a polarizing microscope).

Answer 144

The thin filaments, of diameter 6 nm and length 1.05 um, are rooted in the Z line and form the pale I band (isotropic band); the latter is only approximately 0.25 um wide because most of the length of the thin filament protrudes into the A band in between the myosin rods. As well as actin, the thin filaments contain the proteins troponin and tropomyosin.

Answer 145

The surface membrane, or sarcolemma, is invaginated opposite the Z line into a series of fine transverse tubules (T tubules), which run into the interior of the cell and thus help to activate the numerous myofibrils almost simultaneously.

Answer 146

The T tubular system is well developed in ventricular myocytes but is scanty in atrial cells.

Answer 147

The internal ends of the T-tubules are closed, so the extracellular fluid is never in direct contact with intracellular fluid.

Answer 148

Sarcoplasmic reticulum

Answer 149

The sarcoplasmic reticulum is developed from endoplasmic reticulum and it consists of a closed set of anastomosing tubules coursing over the myofibrils. The sarcoplasmic tubules expand into flattened sacs called subcarcolemmal cistern near the T-tubules, and in section a T-tubule and adjacent cisterns are often seen as a pair, ord "diad". The cistern contain a store of calcium ions that can be released to activate the contractile machinery.

Answer 150

Contraction of the myocte is caused by shortening of its sarcomeres

Answer 151

Contraction of the myocte is caused by shortening of its sarcomeres. Direct inspection shows that the I bands shorten, but the A band does not. This is one of the key observations indicating that contraction is caused by the thin filaments of the I band sliding into the spaces between the thick filaments of the A band ---the sliding filament mechanism.

Answer 152

The filaments are propelled past each other by the repeated making and breaking of cross bridges between the thin and thick filaments. These cross bridges are actually the heads of myosin molecules, which protrude from the side of the thick filament as illustrated in Fig 3.3

Answer 153

At rest, the actin sites, with which the myosin heads would react, are blocked by tropomyosin. Contraction is initiated by a sudden rise in the concentration of free intracellular calcium ions, which bind to troponin C, a component of the troponin complex. This alters the position of the adjacent chain, allowing the myosin head to bind to the actin. Force and movement is produced by a subsequent change in the angle of this cross bridge (i.e the attached myosin head), after which the head disengages and the process repeats itself at a new actin site. This process occurs at numerous similar sites along the filament, and in this way the thick filament "rows" itself into the space between the thin filaments. The most important point about the whole process from the physiological point of view is that the number of cross bridges formed, and therefore the force of the contraction, depends directly on the concentration of free calcium ions within the myocyte. Fig 3.3

Answer 154

The energy for cross bridge cycling is provided by adenosine triphosphate (ATP) , which is broken down during the process into inorganic phosphate and adenosine disphosphate (ADP) by an ATPase site on the myosin head.

Answer 155

In order to maintain an adequate supply of ATP, the myocyte processes an exceptionally high density of mitochondria, which lie in row between the myofibrils and form 30-35% of the cell volume.

Answer 156

Mechanism of contraction: ATP is manufactured in mitochondria by oxidative phosphorylation, for which oxygen is obligatory, and this is why cardiac performance is directly dependent on coronary blood flow. Cardiac muscle is almost incapable of anaerobic phosphorylation, unlike skeletal muscle.

Answer 157

The release of calcium from the cisternal store, which activated the contractile machinery, is itself triggered by a change in the electrical potential across the cell membrane.

Answer 158

The potential difference between the interior and exterior of a myocyte can be measured by driving a fine microelectrode into the cell (a microelectrode is simply a piece of glass tubing which has been heated, drawn out and filled with a conducting solution). The intracellular electrode is connected to an amplifier and a voltmeter, and the other lead of the voltmeter is connected to an electrode outside the cells.

Answer 159

Resting membrane potential of a work cell: The intracellular potential of the resting myocyte is found to be -60 mV to -90 mV (i.e. 60-90 mV lower than the extracellular potential). In work cels this resting membrane potential is stable until external excitation is applied (see Fig 3.4a), but in sino-atrial (SA) node cells and many conduction fibres it is unstable, drifting towards zero with time. (this more complex situation is considered in section 3.7)

Answer 160

Note the unstable resting potential in the pacemaker cell (SA node). Some purkinje fibres also have unstable resting potentials.

Answer 161

- The high concentration of potassium ions in the intracellular fluid and - the high permeability of the cell membrane to potassium ions compared with other ions.

Answer 162

The intracellular K+ concentration is about 35 times higher than the extracellular K+ concentration, so there is a continuous tendency for K+ to diffuse out of the cell down its concentration gradient. Table 3.1

Answer 163

Because the cell membrane is impermeable to them. Fig 3.5 The outward diffusion of a small number of potassium ions therefore creates a very slight separation of charge, and leaves the cell interior negative with respect to the exterior.

Answer 164

The outward diffusion of a small number of potassium ions therefore creates a very slight separation of charge, and leaves the cell interior negative with respect to the exterior.

Answer 165

Because the electrical charge on a single ion is very large indeed, just one excess negative ion per (10 upphöjt i 15) ion pairs is sufficient to produce the resting potential. A numerical imbalance of this size is of course far too tiny to be detected by chemical methods.

Answer 166

If the negative intracellular potential were big enough, the electrical attraction of the cell interior for the positive potassium ions could fully offset the outward diffusion tendency of the ions, creating a dynamic equilibrium in which there was no further net movement of K+ out of the cell. The electrical potential at which this would happen is called the potassium equilibrium potential.

Answer 167

The equilibrium potential is, by definition, equal in magnitude to the outward-driving effect of the concentration gradient, or chemical potential as it is called; and the latter depends on the ion concentration outside the cell (Co) relative to that inside (Ci).

Answer 168

The exact relation between equilibrium potential of ionic species X (Ex) and the ionic concentration ratio is given by the Nernst equation 3.1 s 40.

Answer 169

Experimentally, it has been found that when the extracellular potassium concentration is increased, as can happen in certain medical conditions, the myocyte resting potential declines (grows less negative) in proportion to the logarithm of the extracellular potassium concentration, as predict by the Nernst equation. In hypokalemia, the devaiton increases because potassium conductance declines. see Fig 3.6

Answer 170

shows that the resting membrane potential always falls a little short of the potassium equilibrium potential. This is due to a small inward current of positively charged ions, mainly sodium ions, which is known as the "inward" background current (i b).

Answer 171

Although the permeability of the resting membrane to sodium is only 1/10th to 1/100th of its permeability to potassium, both the electrical gradient and the chemical gradient for Na+ are directed into the cell, and their sum, the electrochemical gradient drives a small inward current of Na+ into the cell. Tab 3.1 Fig 3.5

Answer 172

The chemical gradient for Na+ are directed into the cell, and their sum, the electrochemical gradient drives a small inward current of Na+ into the cell. As a result, the resting membrane potential is 10-20 mV more positive than the potassium equilibrium potential. Moreover, because the resting potential is not quite negative enough to fully counteract the outward diffusion of K+ ions, there is a continuous trickle of K+ out of the cell, producing an outward background current (ik).

Answer 173

In work cells, the outward current Ik is equal to the inward current Ib, so the resting membrane potential is stable despite the continuous slow exchange of potassium for sodium.

Answer 174

The size of the background currents is given by Ohms' law, which state that current (i) is proportional to the potential difference (delta x V) and to the electrical conductance (g-the reciprocal of resistance): i = g.delta V

Answer 175

In the case of a cell membrane, the conductance is proportional to its ionic permeability. For potassium ions the potential difference driving the current is the difference between the resting membrane potential Em and the potassium equilibrium potential Ek, so the background potassium current ik is, by Ohm's law: se 3.2. s 40. Similarly, the inward background current of sodium ions, ib, is by Ohm's law: se 3.3 s 40

Answer 176

(-94 + 4.1)/1.1 or -82 mV And this is reasonably close to the potential in many work cells.

Answer 177

potassium Unchecked, the concentrations of both potassium and sodium would eventually equilibrate across the cell membrane, leaving the battery flat. This is prevented, however, by active pumps in the sarcolemmal membrane, whose function is to preserve the chemical composition of the interior.

Answer 178

This is prevented, however, by active pumps in the sarcolemmal membrane, whose function is to preserve the chemical composition of the interior.

Answer 179

A sodium-potassium exchange pump simultaneously transport sodium ions out of the cell and potassium ions into the cell, and the pump rate is enhanced by a rise in intracellular Na+ or extracellular K+ koncentration. Fig 3.5

Answer 180

The exchange of Na+ for K+ is not quite 1 for 1; slightly more Na+ are pumped out than K+ in, and the pump is therefore electrogenic.

Answer 181

It must be stressed however, that this effect makes only a minor contribution to the membrane potential; blocking the Na+-K+ pump by ouabain causes only small immediate decrease in membrane potential, because the chief factor generating the resting potential is the potassium concentration gradient. Pumping is an active process and consumes metabolic energy in the form of ATP.

Answer 182

calcium-sodium exchange pump

Answer 183

The entry of the excess Na+ ion contributes to the inward background current. The Na+-Ca2+ exchange is not powered directly by ATP but is driven by the downhill sodium concentration gradient, rather as a water-wheel is turned by a water gradient. It therefore depends indirectly on the Na+-K+ pump, since it is the Na+-K+ pump that set s up the sodium gradient. This point is important for understanding the effects of digoxin.

Answer 184

In addition to the sodium-driven calcium pump, the membrane may also possess a few calcium pumps powered directly by ATP.. Together the calcium pumps maintain the intracellular Ca2+ at an extremely low concentration in resting monocytes, namely 10 -7 M

Answer 185

The action potential, which triggers contraction, is an abrupt reversal of the membrane potential to a positive value. (see Fig 3.4).

Answer 186

In a work cell it is normally initiated by the action potential of an adjacent cell, which draws charge passively from the resting membrane (Fig 3.15) and thereby reduced its potential.

Answer 187

When the potential reaches a threshold value between -70 mV and -60 mV, the membrane's ionic permeability suddenly changes; the cell very rapidly depolarizes (loses its negative charge) and overshoots to a positive potential of +20 mV to +30 mV. The membrane then immediately begins to depolarize, but when it reaches zero to -20 mV it becomes relatively stable for a long period (200-400 ms). This stage is called the "plateau", and it causes the cardiac action potential to last far longer than a nerve or skeletal muscle action potential (1-4 ms). Finally the membrane depolarizes, though only 1/1000th of the rate of depolarization, to regain its resting potential.

Answer 188

Action potentials differ somewhat in form between the various cardiac cells. Atrial potentials last 150 ms and are triangular in most species; ventricular potentials are longer (400 ms) and more rectangular owing to a more distinct plateau at approximately 0 mV; and Purkinje cells have the longest potentials, up to 450 ms, with a distinct initial spike followed by a long plateau at approximately -20 mV.

Answer 189

The action potential is generated by a sequence of changes in sarcolemmal permeability to Na+, Ca2+, and K+, which allows ionic currents to flow passively down their electrochemical gradients. The depolarization spike is caused by an extremely rapid increase in permeability to sodium ions; at the threshold potential, voltage-sensitive sodium channels (fast channels), open very quickly and increase the sodium conductance of the sarcolemma around 100 times (see Fig 3.7 and 3.8) This allows a rapid flux of sodium ions into the cell (the first inward current, i Na) and drives the potential towards the sodium equilibrium potential. Table 3.1

Answer 190

The membrane potential does not quite reach E Na because an outward potassium current is still flowing. The situation at the overshoot is in effect a mirror image of the resting situation, and for sodium:potassium conductance ratio of 10:1. Equation 3.2 predicts an overshoot potential of + 29 mV. The overshoot is brief because the fast channels are self-inactivating. Their patency is controlled by 2 different "gates", which are probably charged intramembranous particles. The "m" or activating gate opens quickly at threshold potential, producing the sudden rise in sodium permeability. The "h" or inactivation gate begins to close at the same time as the m gate opens, but it moves less quickly; it inactivates the channel automatically after a few milliseconds. The membrane potential then begins to fall again, owing to an outward current of K+

Answer 191

This is produced by a small but sustained inward current of positive ions, the second inward current (iSI), which prevent the myocyte from depolarizing rapidly like a nerve. The current consists mainly of calcium ions flowing into the cell down their electrochemical gradient, plus a small contribution from sodium ions.

Answer 192

The calcium current is caused by a rise in sarcolemmal permeability to calcium (see Fig 3.8), which is due to the opening of "slow channels" selectively permeable to calcium ions.

Answer 193

The slow Ca-channles are voltage-contolled channels which begin to activate slowly when the cell depolarizes beyond -35 mV (i.e during rapid depolarization) and they stay open for 200-400 ms. The total conductance of the slow channels is much less than that of the fast sodium channels, and the inward Ca2+ current is quite small, but it is sufficient, almost, to counterbalance the ever-present outward K+ current. In this way it almost stabilizes the potential at 0 mV to -20 mV.

Answer 194

The outward K+ current is itself reduced during the plateau owing to a fall in the membrane permeability to potassium. (Fig 3.8). This can be viewed as an economy measure, minimizing the number of potassium and calcium ions exchanged during the long plateau and so reducing the eventual energy cost of the action potential.

Answer 195

The existence of the two distinct inward currents, i Na and I SI, has been proved by the use of tetrotoxin, which blocks only the fast, sodium channels (see Fig 3.9).

Answer 196

Fig 3.9 also illustrates an important action of adrenaline, namely, it increases the size of the calcium current. This contributes to the increase in contractile force produced by adrenaline-

Answer 197

The inward current during the late part of the part of the plateau may be due partly to sodium ions passing in through the sodium-calcium exchange pump (see earlier). One observation favoring this view is that removal of sodium from the extracellular fluid shortens the plateau phase.

Answer 198

1. The cell is electrically unexcitable, or refractory during the long period of depolarization (200-400 ms), and since active contraction is weakening by the time the cell becomes depolarized and re-excitable. Consequently, the mechanical response of the myocardium is normally confined to a single twitch: a fused series of twitches, such as produce a sustained contraction in skeletal muscle, is not possible in myocardium. A sustained myocardial contraction would of course be fatal. 2. The cardiac action potential does more than just initiate contraction: the plateau phase also directly influences the strength of contraction, because the influx of calcium ions influences the intracellular concentration of calcium. Large plateau currents, such as those stimulated by adrenaline and noradrenaline, are associated with more forceful contractions.

Answer 199

The potassium conductance gradually increases towards the end of the plateau phase (see Fig 3.8) and, as the slow channels inactivate, the outward K+ current begins to dominate, producing depolarization to resting potential.

Answer 200

Ionic currents in a myocardial work cell Inward means from the extracellular to the intracellular compartment.

Answer 201

No; this is to mistake speed for quantity. In reality only about 40 million sodium ions enter a single myocyte during depolarization, and as the cell contains around 200000 million sodium ions, the intracellular concentration increase by only 0.02%. For intracellular potassium, the change is only 0.001% ( see Appendix Ion exchange). The Na+-K+- and Na+-Ca2+ pumps are therefore able to restore the chemical composition of the sarcoplasm for only a modest expenditure of metabolic energy.

Answer 202

The link between electrical excitation and muscle contraction is provided by calcium ions. The arrival of an action potential causes the sarcoplasmic concentration of calcium ions to rise sharply; from 0.1 uM to around 5 uM, and some of the calcium binds to troponin C to activate the contractile proteins. Fig 3.3

Answer 203

The correlation between free intracellular calcium ions and contraction has been elegantly demonstrated by the use of aequorin, a protein extracted from luminescent jelly-fish. Aequorin emits a blue light in the presence of free calcium ions, and she aequorin is microinjected into myocytes, a faint blue flash is emitted immediately before each contraction.

Answer 204

If the free cytosolic calcium ion concentration is increased (e.g. by adrenaline), more cross bridges are activated and contractile forces increases.

Answer 205

- The store of bound calcium in the sarcoplasmic cistern and - The second inward current of the plateau. Right side of Figure 3.11

Answer 206

The cistern of the sarcoplasmic reticulum contain a store of calcium ions linked to special quick-release sites. As the spike of depolarization travels into the cell along the T-tubule, it causes the cistern to release calcium ions from the quick-release sites. Some additional Ca2+ may also be released from sites on the inner surface of the sarcolemma. The ions diffuse the micrometer or so into the sarcomere very rapidly, and the cell begins to develop tension within a few milliseconds. Fig 3.10

Answer 207

Stimulated by the raised sarcoplasmic calcium level, the sarcoplasmic reticulum then actively pumps calcium back into its interiors (see Fig 3.11 left side). In combination with the sarcolemmal Na+-Ca2+ pumps, this reduces the calcium concentration in the sarcoplasm and terminates the contraction.

Answer 208

Autoradiographic studies indicate that the sarcoplasmic reticulum are some distance from the release sites, so stored calcium has then to be transported back to the release sites near the Z lines. This is a relatively slow process taking 200 ms or more during diastole. Because the restocking process i slow, the quantity of calcium available at the release sites (and therefore the force of contraction) is influenced by the interval between beats, as described in section 6.8: The Bowditch effect.

Answer 209

During the plateau, an influx of external calcium ions boosts the intracellular calcium content. Thus, extracellular calcium enhances the contractile force of the heart. This is evidently due to its influx during the second inward current, since the force of myocardial contraction correlated with the size of the current; and if the calcium current is increased by adrenaline, contractile force increases too.

Answer 210

First, the arrival of the extracellular ions in the sarcoplasm helps to stimulate the release of calcium from the internal store, a phenomenon called "calcium-induced calcium release". Second, the influx of extracellular calcium ions increases the amount of intracellular calcium available for re-uptake into the store, which becomes available in subsequent beats.

Answer 211

The size of the intracellular store of calcium depends on the balance between the influx of extracellular calcium ions during the plateau and their expulsion by the sarcolemmal pumps during diastole.

Answer 212

1) the extracellular Ca2+ concentration and 2) the relative duration of systole (the calcium influx phase) and diastole (the calcium efflux phase) This point is considered further in section 6.8 (The Bowditch effect)

Answer 213

By increasing the level of intracellular calcium, as illustrated in Fig 3.12. Its immediately pharmacological action, however, is to slow down the sarcolemmal Na+-K+ exchange pump, by inhibiting the membrane ATPase that powers it. This produces a rise in intracellular sodium concentration and a fall in the sodium gradient across the cell membrane. Since the Ca2+-Na+ exchange pump is itself driven by the sodium gradient (Fig 3.5) calcium expulsion is slowed and calcium accumulate in the cell.

Answer 214

The mammalian heart beat is initiated by the sino-atrial (SA) node, a strip of modified muscle roughly 20 mm long x 4 mm wide in man, located on the posterior wall of the RA close to the super vena cava. Fig 3.13

Answer 215

Because it evolved from the sinus venous, an antechamber to the right atrium in lower vertebrates.

Answer 216

The sinus node is composed of small myocytes with only scanty myofibrils and an electrically unstable cell membrane (see later).

Answer 217

As a result of their unstable resting membrane potential, the nodal cells generate an action potential roughly once every second. This excites the adjacent atrial work cells and a wave of depolarization then spreads across the two atria, passing from cell at a rate of approximately 1 m/s and initiating atrial systole.

Answer 218

After passing down the atrial septum the electrical impulses reaches the atrioventricular node (AV node), which is a small mass of cells and connective tissue situation in the lower, posterior region of the atrial septum.

Answer 219

The AV node marks the start of the only electrical connection across the annulus fibrosis, which otherwise completely insulates the atria from the ventricles.

Answer 220

The impulse is delayed in the node for approximately 0.1 s (at resting heart rates), owing to the complex circuitry of the cells and their small diameter (2-3 um), which reduces the conduction velocity to only 0.05 m/s. The resulting delay is functionally very important because it allows the atria sufficient time to contract before the ventricles are activated.

Answer 221

A bundle of fast-conducting muscle fibers, called the bundle of His, next conveys the electrical impulse from the AV node across the annulus fibrosis into the fibrous upper part of the interventricular septum. Here the bundle turn forwards and runs along the crest of the muscular septum (see fig 3.13) , giving off the so-called "left bundle branch" which really comprises 2 sets of fibres, one anterior and one posterior. These course down the left side of the septum to supply the left ventricle. The remaining bundle, the right bundle branch, runs down the right side of the septum and supplies the right ventricle.

Answer 222

The bundle fibres are wide, fast-conducting myocytes arranged in a regular end-to-end fashion. They terminate in an extensive network of large fibres in the subendocardium which were described by the Hungarian histologist Purkinje.

Answer 223

The Purkinje fibres are the widest cells in the heart and their large diameter (40-80 um) endows them with a high conduction velocity (3-5 m/s); their role is to distribute the electrical impulse rapidly to the endocardial work cells. From the endocardium the impulse spreads from work cell to work cell as approximately 0.5-1 m/s, and excite the whole ventricular mass as near simultaneously as possible.

Answer 224

The SA node normally sets the heart rate simply because its cells have the fastest intrinsic rate of firing and thus "get there first". The cells of the bundle of His are also capable of spontaneous firing, albeit at the slower rate of 40 per min and some Purkinje cells can generate their own rhythm too, though even more slowly (approximately 15 per min). There is thus a gradient of intrinsic firing rates along the electrical system. The lower cells are normally excited from the SA node, however, before they have time to fire spontaneously, and this is called "dominance" by the SA node.

Answer 225

The existence of an alternative, albeit slower pacemaker is revealed in a pathological condition called "heart block", in which there is a blockage of the normal electrical connection across the annulus fibrosis. This prevents the SA node from dominating the bundle of His, and cells in the bundle then take over the pacemaker role, driving the ventricles at their own intrinsic rate of about 40 beats/min.

Answer 226

Myocytes can be divided into work cells with stable resting membrane potentials and pacemaker cells with unstable membrane potentials.

Answer 227

The resting membrane potential of a SA node cell is only about -60 mV, and it decays spontaneously as illustrated in Fig 3.4 and 3.14

Answer 228

This slowly declining potential is called the pacemaker potential (pr pre-potential) and when it reaches threshold (approximately -40 mV in nodal cells) it triggers an action potential, which sparks off the next heart beat.

Answer 229

The slope of the pacemaker potential determines the time taken to reach the threshold value, so the slope governs heart rate; the steeper the slope the sooner threshold is reached and the shorter the time between beats.

Answer 230

Since the pacemaker slope is steeper in SA node cells than elsewhere in the electrical system, the SA node has the highest intrinsic firing rate and initiates each heart beat.

Answer 231

The decay of the pacemaker potential is caused by a gradual fall in membrane permeability to potassium ions, which is reflected in a fall in total membrane conductance (see Fig 3.7).

Answer 232

As a result, the outward background current iK falls progressively, allowing the inward background current (termed if in nodal cells) to depolarize the cell slowly (see Fig 3.14).

Answer 233

As the potential approaches -40 mV, some low-threshold voltage-gated channels permeable to calcium ions begin to open, so a small inward current of Ca2+ ions contributes to the final third of the pacemaker potential

Answer 234

This is because the nodal cell lacks functional fast sodium channels, its action potential is generated solely by isI, the slow inward current of predominantly calcium ions. See table 3.3.

Answer 235

The spread of excitation from the SA node into the atria, conduction system and ventricles is mediated by local electrical currents acting ahead of the action potential. In the active depolarized region, the exterior of the cell membrane is negatively charged with respect to the interior, while in the resting zone ahead it is positively charged (see Fig 3.15).

Answer 236

The 2 regions are connected by a conducting medium; the extracellular fluid, so positive charge flows in the opposite direction along the cell axis via the gap junctions of the intercalated discs and depolarizes the inside of the membrane. The process is in fact the discharging of a capacitor, the lipid cell membrane. When the resting membrane has been depolarized to threshold it generates an action potential and the entire process moves on: and since the membrane to the rear is refractory, the excitation progresses unidirectionally.

Answer 237

The rate of conduction is greater in wider cells, because they have a lower axial resistance. It is also great in cells with large, rapid rising action potentials, because these create bigger propagating currents.

Answer 238

Nervous control of heart rate: The pacemaker is innervated by autonomic nerves and its intrinsic rate is continuously modified by activity in these nerved.

Answer 239

Increased activity in the sympathetic nerves innervating the SA node speeds up the heart rate (tachycardia), while increased activity of the parasympathetic nerves slows it down (bradycardia).

Answer 240

Sympathetic and parasympathetic fibers also innervate the AV node, shortening or lengthening the transmission delay respectively.

Answer 241

Both sets of autonomic nerve are continuously active at rest but vagal inhibition predominated: if both systems are blocked the intrinsic heart rate turns out to be around 105 beats/min in a young adult.

Answer 242

Physiological alterations of heart rate are usually due to reciprocal changes in autonomic nerve activity; for example; the tachycardia of exercise is induced by both an increase in sympathetic activity and a simultaneous decrease in vagal activity.

Answer 243

Pacemaker rate is also sensitive to temperature, and during a fever the heart rate increases by approximately 10 beats/min per celsius. The temperature effect is put to practical use during open heart surgery, where cooling is used to slow the heart.

Answer 244

The parasympathetic nerve terminals act by releasing a neurotransmitter substance called acethylcholine, which bind to receptor molecules in the cell membrane, the muscarinic receptors.

Answer 245

1) The pacemaker potential becomes more negative (hyper polarization) and 2) The rate of upward drift of the pacemaker potential is reduced. See Fig 3.16. As a result of these 2 changes, the potential takes longer to reach threshold and the internal between beats increases.

Answer 246

The hyperpolarization is induces by a rise in membrane permeability to potassium due to the opening of additional K+ channels; this increased the outward background current and shift the membrane potential closer towards the potassium equilibrium potential. The opening of the additional K+ channels is mediated by an intramembrane protein called a G-protein, which may directly link the muscarinic receptor to the K+ channels.

Answer 247

The reduced slope of the pacemaker potential is due to a reduction in the depolarizing inward current i nersänkt f; the effect on slope lasts longer than the hyper polarization, and this is not yet fully understood.

Answer 248

Sinus arrhythmia; slowing of the heart during each expiration. Slowing of the heart at the onset of fainting and during diving. An extreme example of vagal bradycardia has been given rise to an everyday expression; playing possum; to fool its attachers the opossum feint death by collapsing with a profound bradycardia.

Answer 249

The sympathetic nerve terminals act by releasing the neurotransmitter noradrenaline (norepinephrine in the American literature).

Answer 250

Beta 1 adrenoreceptors

Answer 251

The hormone adrenaline (epinephrine) acts similarly. Adrenaline and noradrenaline, known collectively as the catecholamines, not only increase the HR (their chronotropic action) but also increase the force of myocardial contraction (inotropic action).

Answer 252

Due to an increase in the inward background current i f (nersänkt f), which is carried by Na+ and Ca2+ ions. See fig 3.17

Answer 253

1: They shorten all the conduction delay in the AV node 2: They shorten the plateau of the work cell action potential by increasing the outward potassium current; this shortens systole 3: They increase the rate of relaxation of myocytes by stimulating the cisternal pumps to take up free cytosolic Ca2+ more rapidly. These additional effects help to preserve the diastolic period available for refilling.

Answer 254

``` The inotropic (stengthening) effect of the catecholamines is mediated by an increase in the inward calcium current during the plateau. This enhances the intracellular calcium store over the course of several beats. (see Fig 3.9 and 3.17). ```

Answer 255

The effects of beta-adrenoreceptor activation seem to be mediated by an intramembrane protein, the Gs-protein, which activates a membrane-bound enzyme, adenylate cyclase. The latter catalyses the formation of an intracellular "second messenger", cyclic adenosine monophosphate (cAMP), which activated protein kinase.

Answer 256

Protein kinase is an intracellular enzyme which, via phosphorylation, influences the number of functional calcium channels in the sarcolemma, and the activity of the cisternal calcium pumps.

Answer 257

Severe extracellular electrolyte disturbances will in general be "A bad thing" for cardiac function. Hypocalcemia reduced myocardial contractility, while extreme hypercalcemia arrest the heart in systole. But it is probably hyperkalemia (a raised concentration of extracellular potassium ions) that is most often a problem in clinical practice.

Answer 258

The normal potassium concentration in extracellular fluid is 3.5-5.5 mV, and a level of only 7.5 mM K+ can arrest the heart in diastole.

Answer 259

Chronic hyperkalemia can arise gradually during renal failure, acidosis or potassium overloading and its direct effect is to reduce the resting membrane potential by lowering the potassium equilibrium potential. See Fig 3.6 The action potential is altered too, because the gradual redcution in resting potential allows plenty of time for the inactivation gates (h gates) of the fast Na+ channels to close.

Answer 260

At a resting potential of -70 mV, about half of the h gates are closed, while at -50 mV they are all closed. As a result the action potential has a sluggish rise and a small amplitude (see Fig 3.18)

Answer 261

Small action potentials produce only small propagating currents, so the conduction of a small action potential is easily blocked, leading to arrhythmias and heart block. Moreover, the action potential becomes shorter, which reduced the total influx of Ca+ ions and leads to a weakening of the heart beat.

Answer 262

Some drugs affecting cardiac electricity: The actions of many anti-arrhythmic drugs (e.g. quinidine, procainamide, lignocaine) are still ill-understood, but two classes of drug, beta-adrenoreceptor blockers and calcium-channel blockers, are better understood.

Answer 263

General beta-antagonists like propranolol and oxprenolol, and selective beta1-antagonists like atenolol and metoprolol, block the beta1-adrenoreceptors on nodal and work cells. This interrupt the tonic sympathetic drive to the heart, reducing heart rate and contractile force. Since this also reduced cardiac output and work, beta blockers are often used in the treatment of hypertension (any angina)

Answer 264

Verapamil and nifedipine (the dihydropyridines) are a relatively new class of drug which act chiefly on high-threshold voltage-gated calcium channels involved in the plateau phase (L-type channels). These channels are partially blocked, impairing the slow inward current of Ca2+ ions. This reduced the duration of the action potential and produces a negative inotropic (weakening) effect. These calcium-channel blockers are used to treat certain arrhythmias.

Answer 265

The resting membrane potential approximates to a K+ equilibrium potential, modified by a slight inward background current of Na+. Ionic pumps maintain the intracellular composition but do not directly generate the membrane potential.

Answer 266

The action potential of work cells arises from a rapid inward current of Na+, followed by a slow inward current of (chiefly) calcium ions which gives rise to a prolonged plateau. The potential do not only excites contraction but also influences contractile force, by affecting the intracellular Ca2+ level.

Answer 267

In nodal cells, a decaying pacemaker potential is generated by a decaying potassium conductance. This triggers a sluggish action potential which is generated solely by the slow inward current.

Answer 268

Autonomic nerves adjust heart rate by altering the rate of rise of the pacemaker potential and, in the case of parasympathetic fibres, by increasing the resting membrane potential.

Answer 269

The process of recording the potential changes at the skin surface resulting from the depolarization and depolarization of heart muscle. The spread of excitation through the myocardium involves small currents flowing through the extracellular fluid. See fig 3.15 These extracellular currents create slight potential differences at the body surface because the extracellular fluid is a continuous conducting medium between the heart and skin.

Answer 270

The size of the potential differences at the surface depends on the size of the cardiac extracelllular current, which in turn depends on the mass of myocardium being activated. The minute differences in skin potential (approximately 1 mV) are picked up by metal contact contact electrodes, measured by a millivoltmeter and recorded on a moving paper strip to produce the ECG.

Answer 271

There are 3 main deflections per cardiac cycle; the p-wave, corresponding to atrial depolarization, the QRS complex, corresponding to ventricular depolarization, and the T wave; corresponding to ventricular depolarization.

Answer 272

During ventricular excitation, a large mass of muscle is activated almost synchronously, and this produces a large deflection in the ECG: The QRS complex.

Answer 273

Myocardial ischemia affects not only the ST segment, but also the T wave, causing it to invert.

Answer 274

The size and orientation of the cardiac dipole in the frontal plane change continuously as excitation spreads through the ventricle.

Answer 275

- Myocardial ischema - Ventricular hypertrophy - Irregular rhythms (arrhythmias).

Answer 276

The size of the potential differences at the surface depends on the size of the cardiac extracellular current, which in turn depends on the mass of myocardium being activated. Since the mass of the conduction system is tiny, its depolarization does not register on a surface ECG, though nodal and bundle activity can be recorded from an intracardiac electrode introduced by cardiac catheterization. With the usual surface ECG, however, only the activity of atrial and ventricular working muscle is detected.

Answer 277

The 2 regions where the trace returns to baseline (the isoelectric state) are called the PR interval and ST segment. These ECG features are compared with the underlying cardiac action potentials in Fig 4.3 and with the mechanical events of the cycle in Fig 2.3

Answer 278

Fig 4.3 Note that the ECG voltage scale is much smaller than that for the membrane potentials. Note also that the base (dashed line) depolarizes before the apex, which is why the T wave is upright.

Answer 279

The first event of the cardiac cycle, the SA node depolarization, does not register on the ECG because nodal mass is too tiny.

Answer 280

The P wave coincides with the upstrokes of the atrial action potentials, not with contraction, contraction follows during the PR interval.

Answer 281

The time taken for excitation to spread over the atria and through the conduction system to reach the ventricular septum

Answer 282

Much of the PR interval is produced by the delay in conduction through the atrioventricular node, which allows time for atrial systole to develop.

Answer 283

The ECG is isoelectric during the PR interval despite the existence of a potential difference between atria (depolarized) and ventricles (polarized) because the insulating annulus fibrosus breaks the electrical circuit and no current flows.

Answer 284

Decreased hear rate during expiration due to increased vagal discharge. The change is partly a reflex from pulmonary stretch receptors, but it persists in anesthetized animals even when ventilation is paralyzed, so the vagal periodicity also arises centrally. Chapter 13

Answer 285

Because the descending diaphragm pulls the heart into a more vertical orientation

Answer 286

Premature beat: As the ventricle is then refractory; the next impulse from the SA node fails to excite the ventricle and there is a compensatory pause (CP), which the patient may notice. "My heart keeps missing a beat doctor"

Answer 287

The patient may experience sudden faints, such as due to third degree AV block.

Answer 288

Irregular oscillations (f) replace the normal P waves, and the atrial undergo a continuous uncoordinated rippling motion, probably due to a circus mechanism. Excitation is transmitted irregularly to the ventricles producing a highly characteristic radial pulse (upper trace) which i s irregularly irregular in timing, and in amplitude (due to variation in passive filling time.

Answer 289

Ischaemia, anaesthetic overdosage, and electrocution. There is no cardiac output or peripheral pulse, and death follows within minutes.

Answer 290

Since ventricular depolarization coincides with depolarization of atrial cells (see fig 4.3), the latter is masked by the QRS complex.

Answer 291

ST segment: This coincides with the plateau of the ventricular action potential, and rapid ejection occurs during this period.

Answer 292

The first heart sound follows just after the S wave, and the second sound a little after the T wave. Fig 2.3

Answer 293

Since the ventricle is uniformly depolarized, the ST segment is normally isoelectric. If, however, part of the myocardium is damaged by ischemia (a poor blood supply), there is an apparent depression of the ST segment, a useful clinical sign in people. Fig 4.9g

Answer 294

The electrical effect of ischemia is to reduce the resting potential of the hypoxic myocytes, and since ventricular polarization is then non-uniform, a current, called the resting injury current, flows between the healthy myocytes and ischemic cells. This shifts the baseline of the ECG (i.e the T-P and P-R regions) and leave the ST segment apparently depressed relative to the new baseline.

Answer 295

The myocytes of the base and epicardium have briefer action potential than the myocytes of the apex and endocardium. See fig 4.3. Repolarization therefore begins in the base and epicardium, followed by the apex and endocardium. Depolarization on the other hand spreads from apex and endocardium to base and epicardium. See Fig 4.4. Thus depolarization occurs in reverse sequence to depolarization, producing the upright T wave.

Answer 296

People: Myocardial ischemia affects not only the ST segment but also the T wave, causing it to invert. See Fig 4.9g

Answer 297

1) The position of the recording electrodes relative to the heart. 2) The concept of the heart as an electrical dipole 3) The changes in dipole orientation during excitation.

Answer 298

Taking the electrode positions first, the ECG is routinely recorded via three electrodes, one on each arm and one on the left leg. In addition, recordings are commonly made from electrodes on the chest wall (the six unipolar precordial leads) but these will not be described here, since our primary concern is with general principles rather than detailed clinical practice.

Answer 299

Right arm-Left arm= lead I Right arm-Left leg = lead II Left arm-Left leg = lead III

Answer 300

Einthoven's triangle

Answer 301

Frontal plane

Answer 302

Lead 1 forms the top of the triangle, oriented horizontally across the chest, and this angle is taken as zero

Answer 303

Lead II is oriented more vertically, at roughly 60 grader to lead I, and lead III at roughly 120 grader.

Answer 304

The electronics are arranged so that an upward deflection occurs when the positive pole of a potential difference is directed towards the left arm (lead I) or left leg (leads II and III). We must therefore consider the overall polarity of the heart during excitation.

Answer 305

At any one instant during the spread of excitation through the ventricle, there exists a resting zone with a diffuse cloud of positive extracellular charges (see Fig 4.6a). Just as a diffuse mass can be represented by a centre of gravity, so a diffuse charge can be represented as a singel charge at its electrical centre or pole. During the spread of excitation, the heart has 2 such poles, one negative and one positive; it is an electrical dipole.

Answer 306

It will register no difference in potential. See Fig 4.6b This extreme case highlights a crucial point; The potential difference actually recorded depends on the orientation of the recording electrodes relative to the dipole. This is because a dipole is a vector quantity having direction as well as magnitude.

Answer 307

An arrow whose length represents vector size and whose direction represents the vector's angle.

Answer 308

Like a force vector, the cardiac vector can be resolved into 2 components at right angles and it is the magnitude of the component directed at the recording lead which is actually registered. See fig 4.6c.

Answer 309

he size and orientation of the cardiac dipole in the frontal plane changes continuously as excitation spreads through the ventricles. (For simplicity, only orientations in the frontal plane are described her, but as the ventricles are 3-dimensional bodies lying in an oblique, rotated position, the dipole rawly lies purely in the frontal plane).

Answer 310

1. The left side of the inter ventricular septum, activated by the left bundle branch. See fig 4.7 This creates a small dipole directed to the right, about 120 grader to the horizontal. 2. Next, the remaining septum and most of the endocardium depolarize. The epicardium is still polarized and the bulky left ventricle predominates, creating a large dipole directed to the left, about 60 grader to the horizontal. The last region to be excited is the base of the ventricles close to the annulus fibosus, so the final dipole is small and directed upwards. As Fig 4.7 shows, this sequence of ventricular activation causes the cardiac vector to swing round in an anti-clockwise direction, and to wax and wane in size over approximately 90 ms.

Answer 311

Why the QRS complex is complex: From the lead positions and vector sequence it is possible to understand why the QRS wave contains negative waves and why the QRS complex differs from lead to lead. As a simple example; consider the ventricular dipole at three instants; the beginning, middle and end of excitation, as seen be leads I and III. In the particular case illustrated in Fig 4.8, the small initial dipole at approximately 120 grader is directed obliquely away from lead I. Resolving the vector, we find a small component directed at 180 grader, which isin the opposite direction to lead I (0 grader), so lead I records a small negative deflection or Q wave. At the same instant lead III (120 grader) records a positive deflection ---the beginning of an R wave, with no preaching Q wave. After 50 ms, the dipole has a large component directed at lead I, which records a large upward deflection, the R wave. Lead III is a t right angles to the dipole at this instant, and so records zero potential difference. By 90 ms the dipole has swung round to -100 grader, in the case illustrated, amusing small negative deflection in both leads I and III, i.e. S wave. Thus, the same event produced a QRS complex in lead I, but an RS complex in lead III. It must be emphasized that there are many variations from the pattern illustrated owing to variations in cardiac orientation. See Fig 4.8

Answer 312

n of the largest dipole is called the electrical axis of the heart, and in Fig 4.7 this is about 60 grader below the horizontal. The electrical axis can be estimated roughly by comparing the size of the R wave in leads I, II, and III. If for example the largest R wave is in Lead II, the electrical axis is closer to 60 grader than to 0 grader or 120 grader. Conversely, the lead with the smallest QRS complex and R and S waves of nearly equal height lies roughly at right angles to the electrical axis.

Answer 313

The normal range for the electrical axis is very wide; from -30 to + 110 grader. It depends partly on the anatomical orientation of the heart in the chest, being more vertical in a tall person with a narrow thorax. It also becomes more vertical during each inspiration as the pericardium is pulled down by the descending diaphragm. See Fig 4.9a. The axis depends too on the relative thickness of the wall of the right and left ventricles.

Answer 314

The axis depends too on the relative thickness of the wall of the right and left ventricles. Hypertrophy of the left ventricle shift the electrical axis to the left (left axis deviation), while hypertrophy of the right ventricle produces right axis deviation.

Answer 315

A phasic rise in vagal activity during expiration, and it is especially marked in children an young adults.

Answer 316

-Ectopic beats. -Heart block (main bunds or a bundle branch may fail to conduct normally) Complete heart block kan cause a sudden collapse, called a Stokes-Adam attack. -An abnormal conduction pathway may allow the wave of excitation to travel in a circle (circus): the circle causes a recurring re-entry of excitation just after myoctytes emerge from their refractory period; so the process becomes self-perpetuating. The circus mechanism may underlie the relatively harmless condition of atrial fibrillation. See Fig 4.9f and the rapidly fatal condition of ventricular fibrillation. A classic example of the circus process is provided by the Wolff-Parkonson-White syndrome Fig 4.9

Answer 317

A classic example of the circus process is provided by the Wolff-Parkonson-White syndrome, which is characterized by episodes of paroxysmal tachycardia or "palpitations" where the ventricles beat at over 200 per min. The syndrome is caused by an anomalous electrical connection across the annulus fibrosus called the bundle of Kent, which allows the ventricular excitation wave to re-enter the atrial and re-excite the AV node prematurely.

Answer 318

Drugs like quinidine and procainamide prolong the refractory period, which renders re-entry more difficult and terminates some circus arrhythmias. The calcium blocker verapamil shortens the action potential and upsets the timing of re-entry, so it too can terminate a circus movement.

Answer 319

The volume of blood ejected by one ventricle in one minute: it equals the stroke volume multiplied by heart rate.

Answer 320

In human subjects the output can be measured by a variety of methods, which either measure the cardiac output as a whole (The Fick principle and the dilution methods) or measure stroke volume and heart rate separately (Doppler and radionuclide methods). The output can also be assessed indirectly by echo and by examining a subject's peripheral pulse. Ina anesthetized animals, direct methods requiring surgery can also be employed, such as the placing of an electromagnetic flow meter around the aorta. This chapter concentrate on the methods which are currently most important in medicine: beginning with the gold standard method based on Fick's principle.

Answer 321

The rate at which the circulation takes up oxygen from the lungs kust equal the change in oxygen concentration in the pulmonary blood multiplied by the pulmonary blood flow. Since the pulmonary blood flow is of course the output of the right ventricle, this offers a way of determining the cardiac output.

Answer 322

The amount of oxygen carried into the lungs in venous blood per minute is the blood flow times venous oxygen concentration

Answer 323

O2 in venous blood entering the lungs per minute: se formel s 70

Answer 324

Similarly: the amount of oxygen carried out of the lungs per minute in the blood equals blood flow times arterial oxygen concentration.

Answer 325

O2 in arterial blood leaving the lungs per minute: se formel s 70

Answer 326

se formel s 70 In a steady state, this oxygen uptake must equal the loss of oxygen from the alveolar gas in the lungs over one minute (V O2) Oxygen consumption by the alveolar cells can be neglected.

Answer 327

Alveolar oxygen removed per min = blood oxygen gained per min . Or in terms of the arteriovenous concentration difference: Ca-Cv

Answer 328

V o2 = Q x (Ca-Cv). This is Fick's expression, and it tells us that the rate of oxygen uptake from alveolar gas (ml/min) equals pulmonary blood flow (litres/min) times the arteriovenous difference in oxygen concentration (ml/litre) Since pulmonary blood flow is actually the output of the right ventricle, we can rearrange the Fick expression to give the cardiac output.

Answer 329

Oxygen uptake rate (ml/min)/ ArterialO2 conc-VenousO2 conc (ml/l) Se s 70 se ex s 70 hur det här kan räknas ut/användas.

Answer 330

Because their oxygen concentration varies: It is 170 ml per litre in renal venous blood, but only 70 ml per litre in coronary venous blood. Venous blood only becomes fully mixed and uniform in the right ventricle outflow tract and pulmonary artery. The problem of obtaining a sample of fully mixed venous blood was finally solved in 1929, when a german physician passes a ureteric catheter through his own arm vein and into the right heart; watching its progress on an x-ray screen.

Answer 331

The subject's resting oxygen consumption is measured over 5 to 10 min by spirometry, or by collection of expired air in a Douglas bag. During this period, an arterial blood sample is taken from the brachial radial or femoral artery, and a mixed venous sample is taken from the pulmonary artery or right ventricle outflow tract by a cardiac catheter, introduce through the antecubital vein. The oxygen content of each blood sample is measured and the cardiac output calculated as above.

Answer 332

It is slow, and beat-by-beat changes in stroke volume cannot be followed. The method is only valid in the steady state, so the transient early response to exercise cannot be measured. The method is invasive, and cannot be used during severe exercise because the cardiac catheter may provoke arrhythmias in a violently beating heart. An indirect version, in which catheterization is avoided and Cv estimated by analysis of rebreathed gas, is less accurate and rarely used today.

Answer 333

J = Q (C out-C in) Se s 71. Q med prick över. In physiology, Fick's principle is widely used to work out the rate at which an organ consumes nutrients like glucose or fatty acids, from measurements of blood flow and the arteriovenous concentration difference for the nutrient.

Answer 334

In Hamilton's indicator dilution method, a known mass of a foreign substance (the indicator) is injected rapidly into a central vein or into the right heart. The indicator must be one that is confined to the bloodstream and easy to assay; for example the dye indocyanine green, or albumin labelled with radio iodine. The bolus of indicator becomes diluted in the returning venous blood, passes through the heart and lungs, and is ejected into the systemic arteries (see Fig 5.2 a). Samples of arterial blood are taken at frequent intervals from the radial or femoral artery, and the concentration of the indicator in the arterial plasma is plotted against time.

Answer 335

1) The time t needed for the bolus to pass a given point. 2) The average concentration of indicator in the bolus over that period. Concentration C, is by definition the injected mass, m, divided by the volume of plasma, V, in which the indicator became distributed: C= m/V.

Answer 336

If this volume takes t seconds to pass a fixed point, the left ventricle evidently pumps plasma along at rate V/t (2 litres in 20 s in Fig 5.2b, or 6 litres/min.

Answer 337

Cardiac output of plasma= V/t = mass of indicator m/mean concentration C x time t Se se 72 The output of blood is then easily calculated, being the output of plasma divided by l-haemotocrit (haemotocrit is the fraction of blood consisting of cells).

Answer 338

The output of blood is then easily calculated, being the output of plasma divided by 1-haemotocrit (haemotocrit is the fraction of blood consisting of cells).

Answer 339

mass of indicator/Area under C-t curve. In reality the C-t plot is not of course a square wave, it is a curve which rises to a peak and decays exponentially. See Fig 5.2c, but the above expression still applies. The exponential decay is caused by the ventricle ejecting only a fraction of its content with each systole, leaving some indicators behind. Indicator-free venous blood returning to the hart during each diastole dilutes the residual indicator, and this in turn is only partially ejected in the next systole, and so on. After about 15 s, however, the decay curve is disrupted by a "recirculation hump". This is caused by blood of high indicator concentration returning to the heart after completing one transit of the myocardial circulation (the shortest route back). To apply the above dilution equation, we must find the area under a C-t curve uncomplicated by recirculation, and this is done by extrapolating the early part of the decay curve, before the recirculation hump. A semi-logarithmic plot facilitates the extrapolation, because it converts the the exponential decay into a straight line; the latter is then extrapolated to a negligible concentration (conventionally 1% of the peak value) as in Figure 5.2c. The area under the corrected C-t curve is computed and used to calculate cardiac output. Pros and cons: the results agree with Fick's direct method to +/- 5%. The dilution method has an improved time resolution (30 s, cf.> 5 min for Fick's method) and can be used in exercise, since ventricular catheterization is not required. The error involved in extrapolating the decay curve may be short and distort, this can be a serious limitation.

Answer 340

This variant of the dilution method is widely used in cardiac departments. Instead of a foreign chemical, temperature is used as the indicator. A known volume of cold saline is injected quickly into the right atrium, right ventricle or pulmonary artery, and the dilution of the cold saline by warm blood is recorded by a thermistor-tipped catheter (Swan-ganz catheter) in the more distal pulmonary artery. Cardiac output can then be calculated from the area under the temperature-time plot from and the amount of heat (i.e. cold) injected.

Answer 341

The recirculation problem is circumvented because the saline warms up to body temperature long before it returns to the right side. Another advantage is that the ejection fraction can be calculated from the step rise in temperature that follows each refilling of the heart by warm blood.

Answer 342

Heat transfer across the walls of the right ventricle and pulmonary artery, which can cause over-estimation of the distribution volume and therefore cardiac output; a computed correction is usually made for this.

Answer 343

This is an increasingly popular method in which a pulse of ultrasound is directed down the ascending aorta from a transmitter crystal at the suprasternal notch. Some of the ultrasound is reflected back by the red cells, and this is collected and analysed. Since the cells have a high velocity, the frequency of the returning sound waves is different from that of the transmitted signal; this is the Doppler effect, analogue to the change in pitch of a car siren as it speeds past.

Answer 344

Pulsed Doppler method: The average blood velocity across the aorta at each instant is computed from the spectrum of frequencies in the returning signal, and the velocity is plotted against time as in Figure 5.3. To convert the time-averaged velocity (cm/s) to flow (cm3/s) the diameter of the aorta must be measured by echo (see section 2.5) and the cross-sectional area (pi x r upphöjd i 2) then multiplied by mean velocity. The result, aortic flow, represents cardiac output minus coronary blood flow. Although the Doppler method has calibration and "noise" problems, it has the enormous advantages of non-invasiveness and speed, and can record each individual ejection.

Answer 345

See Fig 5.3 s 75

Answer 346

It is to lay a finger on the radial pulse. HR can be measured, and the finger also senses whether the pulse is sting or weak, a strong pulse being associated with a large stroke volume (e.g.exercise) and a weak pulse associated with a low stroke volume (e.g hemorrhage).

Answer 347

What the finger actually detects is the expansion of the artery as pressure rises during systole. The rise in pressure, or "pulse pressure" equals systolic pressure minus diastolic pressure, and this is easily measure with a sphygmomanometer.

Answer 348

Most of the stroke volume (70-80%) is temporarily accommodated in the elastic arteries, owing to the resistance of the arteriolar system to runoff. The dissension of the elastic arteries raises the blood pressure, and the amount by which pressure rises depends partly on the stroke volume and partly on the distensibility in the arterial system.

Answer 349

As change in volume per unit change in pressure

Answer 350

See Fig 5.4 s 76

Answer 351

Compliance = increase in volume/ increase in pressure Rearranging this, we can see how pulse-pressure related to stroke volume

Answer 352

Pulse pressure = Stroke volume (minus initial runoff)/compliance

Answer 353

1) High arterial pressures and volumes reduce arterial compliance; this is evident from the curvature of the arterial pressure-volume relation in Fig 5.4. 2) High ejection velocities reduce compliance because the artery wall is a viscoelastic material (see Appendix) and needs time to expand. During exercise the pulse pressure increases proportionately more than stroke volume because there is less time available for viscous relaxation in the wall. 3) Advancing age is associated with arteriosclerosis, a hardening of the artery walls, which reduces compliance and leads to large pulse pressures in the elderly

Answer 354

Because arterial compliance is so variable, and also because the percentage runoff during early systole with peripheral resistance, the pulse pressure offers only an indirect assessment of stroke volume. Nevertheless, within its limitations the peripheral pulse provides an exceedingly convenient indication of changes in cardiac output in an individual patient from day to day.

Answer 355

An iv injection of radionuclide is given and the number of counts emanating from the ventricles is monitored by a precordial gamma camera.

Answer 356

The ejection fraction and stroke volume can be calculated from the difference between the radioactive content of the ventricles in diastole and in systole.

Answer 357

These measurements can be converted into stroke volume if some assumptions are made about chamber shape.

Answer 358

Electromagnetic flowpower: This technique is used only in animal experiments, because it is necessary to place a curved magnet with its poles directly on either side of the aorta or pulmonary artery. Since blood is an electrical conductor, the flowing blood induces an electrical potential as it cuts the magnetic field: the measured potential is proportional to blood velocity (cm/s). The internal diameter of the vessel must be known to convert mean velocity to flow. Being small, this device can be left inside a conscious animal, transmitting a signal by telemetry (radio waves), and in this way much has been learned about the regulation of stroke volume of unfettered exercising animals.

Answer 359

HR and stroke volume, and is usually altered by changes in both factors.

Answer 360

The cardiac output correlates with the body surface area, which is about 1.8 m2 in a 70 kg adult, and the cardiac output per unit surface area (the cardiac index) averages 3 litres/min per m2. In everyday life, however, the output is continually changing in response to circumstances.

Answer 361

Moving from the lying position to standing reduces CO by approximately 20%, while sleep reduces it by approximately 10%. A heavy protein meal or excitement and fear can increase the output by 20-30%. Pregnancy gradually raises the output by 40%.

Answer 362

Heavy exercise causes the greatest increase, by as much as 4 times in untrained students and 6 times in Olympic athletes. Diseased heart, on the other hand have a much more restricted range of outputs. Table 6.1

Answer 363

After a hemorrhage, for example, HR increases while stroke volume decreases.

Answer 364

The autonomic nerves controlling HR are described in chapter 5, chapter 6 concentrates on the control of stroke volume and its coordination with HR and vascular factors to determine the CO.

Answer 365

The energy with which the myocytes contract and the arterial pressure against which they have to expel the blood. (see Fig 6.1)

Answer 366

A highly energetic contraction produces a large stroke volume, other being equal, while a high arterial pressure opposes ejection and reduces the stroke volume, other things again being equal. Fig 6.1

Answer 367

1) Stretching the cells during diastole enhances their subsequent contractile energy, and since the stretch of the relaxed ventricle depends on the pressure distending it, contractile energy is regulated indirectly by the ventricular end-diastolic pressure = Starling's law of the heart. 2) The innate strength with which a myocyte contracts from a given initial stretch, or "contractile" as it is called, can be increased by nervous, hormonal and chemical influences, for example, by noradrenaline or extracellular calcium ions.

Answer 368

Because the immediate effect of active tension is not to produce ejection but to raise intraventricular pressure during the isovolumetric phase of the cardiac cycle. (See section 2.2) Ejection cannot begin until ventricular pressure exceeds arterial pressure, and this consumes a substantial part of the energy available per contraction. If arterial pressure is raised, more of the contractile energy is consumed in raising the pressure in the isovolumetric phase and less remains for ejection.

Answer 369

Arterial pressure depends partly on total peripheral resistance (TPR), so any rise in TPR tends to diminish the stroke volume.

Answer 370

1) stretch during diastole, which depends on ventricular end-diastolic pressure 2) contractility, which is modulated by sympathetic nerve activity and other chemical influences 3) arterial pressure, which opposes ejection and is influenced by TPR. See Fig 6.1

Answer 371

An isometric contraction, and is very analogous to isovolumetric contraction in vivo.

Answer 372

The active tension generated during an isometric contraction is found to increase steeply with initial length, as shown by the length-tension relations in Figures 6.2 and 6.3. This demonstrates that stretching the relaxed myocardium enhances its subsequent contractile energy.

Answer 373

Isotonic contraction and the weight is called the afterload?

Answer 374

In intact ventricle, the afterload is related to arterial pressure and ventricular radius.

Answer 375

If the afterload is increased both the velocity of contraction and the amount of shortening are reduced. See Fig 6.2.

Answer 376

If the resting papillary muscle is stretched by raising the preload, and the isotonic contraction repeated, the muscle now contracts with a greater velocity and achieves a greater shortening. These mentioned observations reinforce the conclusion that the energy of contraction of isolated myocardium is a function of the resting fibre length

Answer 377

The sarcomere length-tension relation: The process of stretching a relaxed muscle affects the length of the basic contractile unit, the sarcomere, and this affects its contractile energy.

Answer 378

Studies of sarcomere length by laser diffraction show that maximum contractile energy develops at sarcomere length of 2.2-2.3 um. The sarcomere length in intact hearts at normal end-diastolic pressures (0-9 mmHg) is below this optimal value, so the intact ventricle normally operates on the ascending limb of the length-tension curve. Beyond 2.2-2.3 um, contractile force decays, but it is very difficult to stretch sarcomeres beyond this point, even in vitro, because they become very stiff; it is therefore most unlikely that sarcomere lengths above 2.3 um are ever produced in intact hearts during life.

Answer 379

Part of the explanation is that at sarcomere lengths below 2.0 um, the opposing actin filaments overlap each other, and this interferes with the formation of actin-myosin cross bridges, and hence with force generation. See Fig 6.3 top. When this interference is reduced by stretching the sarcomere to 2.0 um, contractile force increases

Answer 380

Exactly the same actin-actin overlap mechanism operates in skeletal muscle, yet the length-tension curve of cardiac muscle is much steeper than that of skeletal muscle, indicating that some additional factor is at work in the myocardium.

Answer 381

Fig 6.3 The upper curve of Fig 6.3 shows the length-tension relation for skinned fibres when all the potential cross bridges at each sarcomere length are activated by a high Ca2+ bath. A physiological concentration of calcium activates only a fraction of the cross bridges, so tension is reduced (lower curve), and this curve closely resembles that for intact, unskinned fibres. The curve for partially activated fibres is much steeper than that for fully activated fibres and gradually approaches the latter curve as sarcomere length is increased. This indicates that the fraction of potential cross bridges activated by physiological concentrations of Ca 2+ increases the stretch (length-dependent activation)

Answer 382

Length-dependent activation appears to be due to an increase in the sensitivity of the contractile proteins to calcium with stretch, as shown in Figure 6.4

Answer 383

The curve relating active tension to Ca2+ conc in skinned myocytes is shifted to the left when sarcomere length is increased, and there is a substantial reduction in the calcium conc needed to produce 50% of maximal tension. This phenomenon is known as the length-dependence of calcium sensitivity. See Fig 6.4

Answer 384

How the sensitivity to Ca2+ is increased is still under investigation, but there is growing evidence that troponin C may be the length sensor.

Answer 385

The effect of diastolic stretch on the contraction: See fig 6.5: Distension during diastole caused the development of a greater pressure during systole, indicating that the energy of contraction depended on diastolic distension.

Answer 386

Starling showed that diastolic stretch influences stroke volume.

Answer 387

right atrium.

Answer 388

The pressure distending the right ventricle, the right ventricular end-diastolic pressure (RVEDP) is almost equal to the CVP. Similarly, pulmonary vein pressure governs left ventricle end-diastolic pressure, LVEDP. A general term for all these pressures is "filling pressure".

Answer 389

In Starling's classic experiments (see fig 6.6), the isolated heart and lungs of a dog were perfused with wam oxygenated blood from a venous reservois, the height of which above the heart controlled CVP. The aortic pressure opposing outflow from the left ventricle was held constant by a variable resistance called a Starling resistor, and the combine stroke volumes of the two ventricle were recorded by a bell cardiometer. Being isolated and denervated, the heart-lung preparation was free of nervous or hormonal influences. Fig 6.6

Answer 390

1. Active response to central venous pressure: When CVP is increased, ventricular end-diastolic pressure rises, and this increases the end-diastolic volume. (see Fig 6.7a). It should be noted that this effect is non-linear and tails off at high end-diastolic pressures. Fig 6.5b The stretched ventricle develops a greater contractile energy, which results in the ejection of a greater stroke volume, provided mean arterial pressure is fixed.

Answer 391

Although a rise in CVP initially increase the filling pressure only on the right side of the heart, the LV stroke volume increases too within a few beasts because the increased RV output raises the pressure in the pulmonary vessels, which in turn raises the filling pressure for the LV.

Answer 392

The reason is that, since output is transiently reduced by the pressure load while input continues unchanged, the ventricle distends, this increases its contractile energy and restores stroke volume.

Answer 393

A graph whose ordinate is stroke volume or any other measure of contractile energy and whose abscissa is filling pressure or any other index of resting fibre length is called a ventricular function curve, or Starling curve. See Fig 6.8. For the abscissa, CVP is often chosen because human CVP is easily measured by cathetization and is an important regulator of average fibre length. However, its relation to fibre length is indirect and non-linear. Other indices of stretch include RVEDP, LVEDP, ventricular end-diastolic volume measured by echo; all are indirect indices of resting fibre length.

Answer 394

For the ordinate, stroke volume can serve as an index of contractile energy if mean arterial pressure is held constant, as in the heart-lung preparation. However, it obviously takes more energy to eject blood at a high pressure than at a low pressure, and the product of stroke volume and mean arterial pressure (the stroke work) is a better energy index. See Section 6.4.

Answer 395

Stroke volume and stroke work increase as a curvilinear function of CVP between zero and 10 mmHg, forming the ascending limb of the Starling curve. In the human LV in situ, the curve almost reaches a plateau above 10 mmHg LVEDP (see Fig 6.8b). During standing and sitting, human LVEDP is 4-5 mmHg, and the heart is on the ascending limb f the curve, while in a supine subject /LVEDP 8-9 mmHg) the heart operates close to the plateau.

Answer 396

In isolated dog hearts, the curve peaks at about 20 mmHg and then falls off (See Fig 6.8a), but such preparations are probably never completely normal and it si doubted whether human hearts ever reach this descending limb. Stroke voluem declines in the over-distended preparation partly because the distended atrioventricular valves begin to leak and partly because the reduced curvature of the cardiac wall impairs the conversions of active tension into pressure. (Laplace's law)

Answer 397

Yes, except that the LV has slightly higher filling pressures. See Fig 6.8 and Table 2.1 This is because the LV has thicker, less distensible walls, and LVEDP has to be 4-5 mmHg higher than RVEDP to produce an equivalent stretch and output.

Answer 398

The results shown in Fig 6.8 establish that the greater the stretch of the ventricle in diastole, the greater the stroke work achieved in systole.

Answer 399

"The energy of contraction of a cardiac muscle fibre, like that of a skeletal muscle fibre, is proportional to the initial fibre length at rest" This deduction now honoured as Starling's law of the heart, has been amply confirmed by the direct studies illustrated in Fig 6.2 and 6.3

Answer 400

When one attempts to relate the pumping behavior of the intact ventricle to the contractile properties of isolated muscle, the radius of the cavity is important as all as CVP and arterial pressure. In any hollow chamber it is the radius that relates wall tension to internal pressure, as pointed out in 1806 by Laplace (a french mathematician).

Answer 401

Laplace's law states that the pressure P within a sphere is proportional to the wall tension (which equals stress, S, times wall thickness, w), and is inversely proportional to the radius, r.

Answer 402

(See Fig 6.9); as radius increases, curvature is reduced, so a smaller component of the wall tension is angled towards the cavity, generating less pressure. Thus, the curvature of the ventricle wall determines how effectively the active wall tension is converted into intraventricular pressure.

Answer 403

Since the Frank- Starling mechanism requires some increase in chamber size, it also involves a small fall in mechanical efficiency, and this becomes a dominating effect in grossly dilated, failing hearts. (See Chapter 15)

Answer 404

See Fig 6.9

Answer 405

Laplace's law can be re-arranged to give S = Pr/2W, and this form helps us to understand what governs the afterload on myoctyres in an intact heart.

Answer 406

The afterload is the stress, S, during systole, and from the statement S= Pr/2W, we can see that it depends not only on arterial pressure but also on chamber radius and wall thickness.

Answer 407

Since both pressure and radius decline in the later stages of ejection, there is a gradual reduction in afterload, which facilitates late ejection. Any contraction in which afterload changes is not a truly isotonic one, and is called auxotonic.

Answer 408

The energy expanded in systole results partly in heat formation and partly in external mechanical work in the form of an increase in the pressure and volume of blood in the arterial system.

Answer 409

Mechanical work is, by definition, the applied force (F) times the distance it moves (L); 1 joule of work equals 1 newton force displaced over 1 metro.

Answer 410

The active force exerted on the blood by the ventricle in systole equals the rise in pressure (delta P times the wall area A, since pressure is force per unit area). If the wall moves an average distance L, a volume (delta x V) equal to L X A is displaced into the aorta. Fig 6.10. Thus, the work performed per beat, or stroke work (W) is (se formel s 87). In other word, stroke work equals the rise in ventricular blood pressure x volume ejected (stroke volume).

Answer 411

Ventricular blood pressure varies throughout the ejection phase, so to evaluate stroke work properly it is necessary to construct a graph of ventricular pressure against volume as in Figure 6.10

Answer 412

Line A-B in a) shows ventricular filling. In the initial rapid-filling phase pressure is falling because elastic recoil of the relaxing ventricle exerts a suction effect. In the later slow-filling phase, a rise in pressure drives the increase in volume, so the line coincides with the passive pressure-volume curve of the relaxed ventricle (see Fig 6.10b).

Answer 413

During isovolumetric contraction (line B-C) the heart is "working" very hard in thevery-day sense of the word (consuming metabolic energy and oxygen to generate force), but since no blood in transported out of the system, the ventricle accomplishes no external work. This phase can be linked to a man trying to push over a house; he accomplishes no external work but consumes a lot of oxygen in the process.

Answer 414

At point C the aortic valve opens; the height of line BC is set by the diastolic arterial pressure. In the ejection phase (C-D) external work is accomplished.

Answer 415

At point D (end systolic pressure) the aortic valve closes, and line D-A represents isovolumetric relaxation. Since the total stroke work is the sum of the pressure gain x displaced volume at each instant, it equals the total area within the pressure-volume loop.

Answer 416

shows how the Frank-Starling mechanism affects the pressure-volume loop. The loop is confined within the 2 lines. The lower confine is the end-diastlic pressure-volume curve as explained above; each contraction begins from this line. The upper confine is the curve relating systolic pressure to end-diastoic volume in a purely isovolumetric contraction (see Fig 6.5b). This line depicts the contractile energy available due to the Frank-Starling mechanism. If ejection were prevented, ventricular pressure would just reach this upper confine.

Answer 417

Loop 1 represents a normal cycle, in which ejection occurs. The aortic valve closes when the end-systolic pressure and volume reach the upper confining line.

Answer 418

In loop 2, the end-diastolic volume has been raised, increasing the contractile energy by the Frank-Starling mechanism. Stroke volume increases, providing that the arterial pressure opposing ejection is prevented from rising.

Answer 419

If, however, the arterial pressure is raised, as in loop 3, more of the available energy goes into raising ventricular pressure and stroke volume decreases, though the stroke work (loop area) is unchanged.

Answer 420

If ejection is prevented totally, as in line 4, stroke volume and stroke work are zero, but maximum systolic pressure is generated.

Answer 421

Because of the Frank-Starling mechanism, ventricular end-diastolic volume has an important effect on stroke work, and the factors that regulate end-diastolic volume are therefore very important physiologically.

Answer 422

Transmural pressure is the internal pressure minus the external pressure (intrathoracic pressure). As noted earlier, ventricular distensibility decreases with stretch (rather like the distensibility of a bicycle tyre), so EDV becomes less and less sensitive to diastolic pressure above 10 mmHg. See Fig 6.10b.

Answer 423

Inspiration thus produces a suction effect around the heart and central veins, enhancing right ventricular filling.

Answer 424

Conversely, when intrathoracic pressure becomes positive, as for example during a forced expiration (Valsalva manoeuvre) ventricular filling is reduced. Pressure outside the ventricle also becomes positive in patients with constrictive pericarditis and pericardial effusion, impairing filling and output.

Answer 425

End-diastolic pressure in the right ventricle is nearly equal to central venous pressure; so the latter plays a key role in regulating stroke volume.

Answer 426

1) Blood volume: About 2/3 of the entire blood volume is located in the venous system, so the greater the blood volume, the greater the average venous pressure. Conversely, hemorrhage or dehydration reduces the blood volume and lowers CVP; unless compensated for by venoconstriction.

Answer 427

Gravity, venous tone the and the muscle pump together govern the distribution of venous blood between peripheral veins and thoracic veins.

Answer 428

In a standing man, gravity redistributes around 500 ml of blood from the intrathoracic vessels into the veins of the lower limbs (venous pooling). This reduces the CVP and stroke volume declines. Conversely, lying down redistributes venous blood from the lower limbs into the thoracic vessels, and stroke volume increases.

Answer 429

Peripheral venous tone: The veins of the skin, kidneys and splanchnic system are innervated by sympathetic nerves capable of exciting venoconstriction. The nervous systems can thus except some control over the proportion of blood in the peripheral veins and thereby influence CVP.

Answer 430

Conversely, ventilation occurs in skin vessels, under hot conditions for reasons of temperature regulation, and incidentally lowers the CVP.

Answer 431

Rhytmic exercise repeatedly compresses the deep veins of the limbs and displaces venous blood centrally. Thus helps to enhance CVP and stroke volume during dynamic exercise. At the opposite extreme, guardsmen standing at attention for long periods in hot whether have an embracing propensity to faint, partly because their muslce pump is inactivated. Combined with gravitational venous pooling and heat-induced venodilation, this reduces the CVP and stroke volume, leading to cerebral hypoperfusion.

Answer 432

During inspiration, intrathoracic pressure becomes more negative and intra-abdominal pressure more positive. This increases the venous pressure gradient from abdomen to thorax and promotes filling of the central veins.

Answer 433

Cardiac output; The pumping action of the heart transfers blood from the venous system into the arterial system, and this not only raises arterial pressure, but also simultaneously lowers the central venous pressure. See Fig 6.11. If uncorrected, the fall in CVP and rise in arterial pressure then act as a brake on output. This important negative effect is considered further in section 6.9

Answer 434

The Frank-starling mechanism has many important effects, the most vital being to balance the outputs of the right and left ventricle. It also contributes to an increase in stroke volume during upright exercise if CVP rises. It mediates postural hypotension (a fall in cardiac output and blood pressure leading to dizziness following a fall in CVP in the upright posture), and the arterial hypotension which follows hemorrhage and other pathological events that lower CVP, and it causes a fall in stroke volume during the Valsalva manoeuvre (forced expiration):

Answer 435

A mere 1% imbalance between the outputs, such as a RV output of 5.05 litres/min and LV output of 5.00 litres/min, would, if sustained, raise the pulmonary blood volume from its normal levels of 0.6 litres to 2.1 litres in half-an-hour, causing pulmonary congestion and edema. In heavy exercise, with outputs around 25 litres/min, a sustained imbalance would be catastrophic within minutes. The Frank-Starling mechanism, however, preserves a balance between the 2 outputs.

Answer 436

If RV output transiently exceeds that from the LV; pulmonary blood volume increases slightly and raises pressure in the pulmonary veins, which constitutes the LV filling pressure. This distends the LV and, by the length-tension mechanism, raises LV output. The opposite happens if LV output transiently exceeds right output, and the 2 outputs are thus kept equal in the long term.

Answer 437

1) Standing up where the RV output drops below the LV output for a few beats. 2) Inspiration; where RV output transiently exceeds the LV output owing to the operation of the respiratory pump and the fall in pulmonary vascular resistance as the lungs expand.

Answer 438

Venous return is the flow of blood into the right side of the heart, and is driven by the pressure drop between the capillaries and central veins.

Answer 439

In the intact circulation venous return must equal the cardiac output in the steady state because the circulation is a closed system of tubes, any inequality can only be transient. If the equality constraint is remembered, the term venous return can be useful. In general, however, it is better to avoid the notion that venous return "controls" cardiac output, because this is a circular (literallyO and unhelpful viewpoint.

Answer 440

In the steady state, venous return is the cardiac output, simply observed in veins rather than arteries. Venous return is thus directly dependent on cardiac output. Centrally venous pressure by contrast is essentially an independet variable and can regulate the stroke volume. Venous return "controls" cardiac output only in the sense that transient inequalities between the 2 alter the CVP.

Answer 441

Fig 6.12; shows how CVP raises the output by the Frank-Starling mechanism, provided HR and arterial pressure are unchanged. The direct hydraulic effect of CVP is, by contrast, to oppose venous return, because a high CVP reduces the pressure gradient driving blood from the capillaries into the great veins.This effect is shown as a "venous return curve" in Guyton's plot. If flow ceased altogether, pressure would in principle equilibrate throughout the circulation to produce a "mean circulatory pressure" (approximately 7 mmHg), so the venous return curve is shown falling to zero flow at approximately 7 mmHg. Since the axes for the output curve and return curve are the same, the 2 curves can be plotted on the same graph.

Answer 442

The point of intersection of the 2 curves; where CVP creates the same output and return. Thys Guy tons's analysis illustrates how CVP acts as the independent variable governing both output and return. Guyton's graphical method can also be used to analyse altered states, as illustrated in Fig 6.12

Answer 443

The venous return curve reflects blood flow from the peripheral vasculature into te central veins; where a high pressure opposes return.

Answer 444

mean circulatory pressure at zero flow.

Answer 445

The Guyton's output curve can be shifted upward by increased contractility or reduced peripheral resistance (not shown) and downwards by impaired contractility, as in heart failure (dashed curve).

Answer 446

The venous return curve is shifted upward if mean circulatory pressure (MCP) is increased by venoconstriction or increased plasma volume; this happens in cardiac failure; due to sympathetic activity and renal retention of fluid.

Answer 447

The new intersection (filled circle) represent the new steady state in cardiac failure; almost normal output achieved at a raised CVP.

Answer 448

So great Dr.Starling, in his Law of the Heart. Said the output was greater if, right at the start. The cardiac fibres were stretched a bit more, so their force of contraction would be more than before. The larger the volume in diastole; the greater the output was likely to be. If the right heart keeps pumping more blood than the left, the lung circuit's congested; the systemic --bereft. Since no-one is healthy with pulmocongestion. The law of Doc. Starling's a splendid suggestion.

Answer 449

The balance of output is made automatic. And blood-volume partition becomes steady-static. When Guardsmen stand stil and blood pools in their feet; Frank-Starling mechanics no longer seem neat. The shift in blood volume impairs C-V-P, which shortens the fibres in diastole. Contractions grow weaker and stroke volume drops. Depressing blood pressure, and down the Guard flops.

Answer 450

But when the heart reaches a much larger size, This leads to heart failure, and often demise. The relevant law is not Starling's alas, But the classical law of Lecompte de Laplace. Your patient is dying in deompensation, so reduce his blood volume or call his relation.

Answer 451

Arterial pressure affects the output of the heart both directly and indirectly.

Answer 452

A high arterial pressure directly opposes ejection. The outflow goes down when the pressure at the outlet is raised. See Fig 6.13. This relation is called "a pump function curve" and its intercepts characterize the power of the pump.

Answer 453

The cardiac pump obeys the same rule; the direct effect of a high arterial pressure is to depress the stroke volume by increasing the proportion of the available energy that is consumed in the isovolumetric contraction phase (compare pressure-volume loops 2 and 3, in Figure 6.10

Answer 454

For example, the stroke volume of failing hearts can be improved by treatment with peripheral vasodilator drugs, which lower vascular resistance and therefore the arterial pressure opposing ejection.

Answer 455

If ventricular end-diastolic volume is not held constant there is a further change after arterial pressure is raised: the decrease in ejection allows ventricular diastolic volume to increase. This enhances contractile energy by the Frank-Starling mechanism and helps to maintain stroke volume, as illustrated in Fig 6.7b. The Frank-Starling mechanism thus displaces the pump curve upwards. (see Fig 6.13, dashed line)

Answer 456

In hearts in situ, a third factor, the baroreceptor reflex, comes into play and leads to a fall in stroke volume. The baroreceptor reflex (is described fully in chapter 13) in brief it is a nervous reflex triggered by a rise in arterial pressure.

Answer 457

The baroreceptor reflex reduced the activity of the cardiac sympathetic nerves diminishing the heart rate and contractility. Fig 6.14.

Answer 458

Direct opposition, Ventricular distension Altered sympathetic drive. And the outcome depends on their balance in the specific situation.

Answer 459

Effect 1: A fall in stroke volume is mediated by increased afterload. Effect 2: A rise in stroke volume is mediated by increased ventricular distension secondary to a transient reduction in stroke volume. Effect 3: A fall in stroke volume is mediated by a reflex reduction in contractility.

Answer 460

Contractility energy is affected by chemical influences outside the myocyte (extrinsic regulation) as well as by resting fibre length (intrinsic regulation).

Answer 461

A change in contractile energy that is not due to changes in fibre length is called a change in contractility. The definition of contractility thus specifically excludes the Frank-Starling mechanism.

Answer 462

The most important natural inotropic (strengthening) agent is noradenaline, the neurotransmitter released from sympathetic nerve terminals within the myocardium; the other main physiological inotropic factors are circulating adrenaline and extracellular Ca2+ ions.

Answer 463

NA is released from sympathetic nerve terminals in the ventricle wall and binds to beta 1 receptors on the myocytes. This leads, via activation of the Gs protein-cAMP sequence (see Sectin 3.8) to an increase in the inward calcium current during the plateau of the action potential, which in turn builds up the intracellular calcium store. Aequorin emission studies show that more free Ca2+ is then liberated from the store during depolarization, increasing the proportion of cross bridges activated and generating a greater contractile force. In addition, the Ca2+ uptake pumps of the SR are accelerated resulting in a shorter systole. The effect of NA is therefore to stimulate a more forceful and shorter systole.

Answer 464

1) ventricular pressure rises more rapidly in the isovolumetric phase, and a higher arterial pressure is produced. The maximum rate of rise of pressure, dP/dt max, can be measured with a transducer-tipped cardiac catheter and may, with caution, be used as an index of myocardial contractility. The need for caution arises from the fact that dP/dtmax is affected also by initial fibre length. See Fig 6.5.

Answer 465

Because both the velocity of contraction and the shortening are enhanced by NA. EF is often used clinically as an indirect index of contractility. The enchanted transfer of blood out of the central veins into the arterial system lowers the filling pressure, so heart size is reduced in diastole as well as systole.

Answer 466

Stroke volume increases transiently as ejection fraction rises but is then limited by the concomitant fall in end-diastolic pressure and rise in arterial pressure.

Answer 467

The duration of systole grows briefer, which helps to preserve diastolic filling time. The shorter ejection time does not significantly curtail stroke volume because the velocity of shortening is increased.

Answer 468

1) ventricular pressure rises more rapidly in the isovolumetric phase, and a higher arterial pressure is produced. 2) Ejection fraction increases 3) Stroke volume increases transiently as EF rises 4) The duration of systole grows briefer, which helps to preserve diastolic filling time

Answer 469

To increase arterial pressure and ejection fraction and to reduce ejection time, EDP and heart size. Stroke volume increases substantially only if the effects on arterial pressure and EDP are offset by peripheral circulatory adjustments (see section 6.9).

Answer 470

In the superior, middle and inferior (stellate) cervical ganglia of the 2 sympathetic chains. See Fig 6.16.

Answer 471

The fibres pass as fine cardiac nerves along the outer surface of the great vessels to reach the heart. The left nerves supply mainly atrial and ventricular muscle while the right nerves supply the pacemaker and conduction system.

Answer 472

The sympathetic firing rate increases in response to exercise, orthostasis (standing up), stress and hemorrhage, so that ejection fraction rises in these conditions.

Answer 473

Sympathetic stimulation augments the contractile energy produced at a given end-diastolic length or pressure. The effect of this is to shift the entire ventricular function curve upwards and make it steeper. See Fig 6.17: A family of "curves" of increased contractility in response to NA release. A change in stroke work can be produced either by movement along one Starling curve (involving a change in filling pressure and contractile energy but not contractility) or by movement from one curve to another curve at constant filling pressure (involving a change in contractility alone). In vivo, both processes usually operates because both the inotropic drive and filling pressure are altered by challenges like exercise and postural change.

Answer 474

This allows ejection pressure and ejection fraction to increase and the latter causes a decrease in end-diastolic volume which limits the growth in stroke volume (as in Fig 6.15).

Answer 475

Stroke work (i.e loop area) increases. During hard dynamic exercise (see Fig 6.18b) not only contractility but also the end-diastolic volume is increased by venoconstriction and the muscle pump, resulting in a much larger rise in stroke volume and stroke work.

Answer 476

Loop 1: Basal state. Loop 2: State of increased contractility: the Frankt-Starling relation is shifted upwards by increased contractility, so a higher ejection pressure is reached and a smaller ESV is attended. Ejection fraction is increased, so EDV falls unless activity regulated. Loop area (stroke work) is increased. Loop 3: During exercise, contractility is raised by sympathetic activity and EDV is raised by peripheral circulatory adjustments (venoconstriciton, muscle pump). The increase in stroke volume is now much greater.

Answer 477

Note on the parasympathetic innervation of myocardium: The vagal nerves innervate the conduction system, and atrial muscle, but the ventricular muscle is not well innervated, except in diving mammals. The vagal neurotransmitter, acetylcholine, binds to muscarinic receptors and exerts a negative inotropic effect (weakening) on atrial contractility.

Answer 478

In the dog, maximal vagal simulation reduces ventricular contractility by 15-25%, and this is associated with a reduction in NA level in the coronary venous blood. It seems that in the dog, the vagal fires terminate close to sympathetic endings and can inhibit the release of NA from these endings.

Answer 479

Yes, but at physiological levels its cardiac effects are small compared with those of the cardiac sympathetic nerves.

Answer 480

catecholamines.

Answer 481

calcium ions do not shorten systole.

Answer 482

Studies with intracellular aequorin show that extracellular Ca2+ and the drugs digoxin, caffeine and theophylline all act by raising the concentration of free sarcomplasmic Ca2+ ions during excitation (see Fig 3.12); this rise is due to an increases store of calcium in the SR. In the longer term, thyroxine too exerts a positive inotropic effect.

Answer 483

They include: acethylcholine, and cholinergic agonists, beta-receptor antagonists such as proparanolol and practolol, calcium-channle blockers like verapamil and nifedipine, and barbiturates and many anesthetics.

Answer 484

Acidosis impairs contractility markedly, and in patients with coronary artery disease, the combination of myocardial hypoxia, and acidosis can seriously reduce the contractility; this results in a feeble cardiac response to exercise. Contractility is also severely impaired in chronic cardiac failure of non-coronary origin.

Answer 485

Inotropic effect of beat frequency (the interval-tension relation): The force of beating increases markedly when the interval between beats is reduced. This is not due to NA release when experimentally induced in isolated papillary muscles.

Answer 486

By the reduction in the time available for the expulsion of intracellular calcium by the surface pumps between beats, which leads to a gradual accumulation of intracellular calcium. See Fig 6.19

Answer 487

The first beat after an interval reduction is weaker rather than stronger, conversely, the first beat after a lengthened interval is stronger rather than weaker. See fig 6.19a.

Answer 488

When a premature depolarization occurs in the human heart due to ectopic beat, the resulting systole is weaker than normal and the beat after the compensatory pause is stronger than usual. See Fig 6.19b. This effect is called: post-extrasystolic potentiation, and the patient often notices it. (my heart gives a jump).

Answer 489

A longer interval between beats allows a more complete transfer of calcium from the uptake sites to the release sites, and therefore a more energetic subsequent contraction.

Answer 490

Cardiac sympathetic nerve activity is the dominating factor regulating contractility in vivo.

Answer 491

1) Any increase in pumping transfers blood from the input (venous) side to the output (arterial) side at a faster rate, lowering end-diastolic pressure and raising arterial pressure, both of which impair stroke volume. See Fig 6.11 2) An increase in artificial pacing rate shortens diastole but not systole, and this curtails the filling time. These effects are so marked that the cardiac output of a resting subject actually declines at high pacing rates. Thus a change in a single drive to output is remarkably ineffective; a coordinated cooperative change in all the controlling factors is needed to alter output significantly.

Answer 492

The cardiac output can be increased by various combinations of tachycardia and increased stroke volume, the precise combination depending on exercise intensity, posture and perhaps species.

Answer 493

In upright exercise, the stroke volume can increase substantially too, by 50-100%. In the supine position however, where stroke volume is already high at rest, changes in stroke volume are slight. Table 6.2

Answer 494

1) At the onset of exercise cardiac sympathetic nerve activity increases and vagal activity decreases. This increases the heart rate and shortens both systole and diastole. Augmented atrial contractility helps to offset the effect of the reduced filling time by increasing the atrial contribution to ventricular filling.

Answer 495

2) Ventricular contractility is increased by cardiac sympathetic activity and to a lesser degree by the secretions of the adrenal medulla. This increases the ejection fraction and stroke volume, as can be seen in the echo of Fig 6.20

Answer 496

Sympathetic vasomotor nerves induce venoconstriction in the splanchnic circulation, and the skeletal muscle pump compresses veins in the limbs. The resulting shift of blood into the central veins prevents CVP from falling as cardiac pumping increases. CVP may even increase by a mmHg or so in man during upright exercis, raising the end-diastolic volume and enabling the Frank-Starling mechanism to contribute to the increase in stroke volume (see Fig 6.18 and 6.20).

Answer 497

Vasodilation in the exercising skeletal muscle reduces the peripheral vascular resistance, which minimizes any rise in arterial pressure --indeed arterial pressure can fall a little at the start of light exercise. This prevents impairment of the stroke volume by a rise in the arterial pressure.

Answer 498

The increased cardiac output of exercise thus involves a coordinated interaction between changes within the heart (rate and contractility) and outside it (CVP and systemic vascular resistance).

Answer 499

Patients with an artificial pacemaker benefit from the reduplication of the cardiac control system.Even at fixed pacing rates, moderate increases in stroke volume can be produced by increased muscle pumping, peripheral vasodilation, and adrenaline enhanced contractility during exercise.

Answer 500

Some of the energy expended in systole is "useful" in the sense that it performs work on an external system; the arteries, while the remainder of the energy appears as heat.

Answer 501

Pressure work and kinetic work: The external, mechanical work takes the form of an increase in the volume, pressure and velocity of blood in the arterial system. The mechanical work involved in displacing a pressurized volume of blood is the product of stroke volume and mean pressure rise (See Section 6.4) and equals the area within the ventricular pressure-volume loop.

Answer 502

It therefore imparts kinetic energy (KE, energy of motion) as well as potential energy.

Answer 503

Kinetic energy depends on velocity v, and mass m, and extra work is required to provide it. The total mechanical work of the heart, WT is therefore: see p 102.

Answer 504

Under resting conditons, where 0.08 kg of blood is ejected at a mean velocity of only 0,5 m/s, the kinetic energy works out at 0.02 kg m2 s-2 or 0.01. For the left ventricle this is merely 1% of the external work at basal outputs, and can be neglected. For the right ventricle on the other hand, kinetic energy constitutes approximately 5% of the mechanical work because the blood velocity in the pulmonary artery is almost the same as in the aorta, whereas the pressure rise (and hence pressure work) is only about 20% as great.

Answer 505

During heavy exercise, the ejection velocity increases greatly in both the pulmonary artery and aorta (to approximately 2.5 m/s), while pressure increases only slightly. Even in the left ventricle, kinetic energy then accounts for up to 14% of the total external work, and in the right ventricle the figure can reach 50%.

Answer 506

Its rate of working, i.e stroke work x heart rate. cardiac power ranges from approximately 1.2 W (J/s) at rest to around 8 W in heavy exercise, which is about a fiftieth the power of a small electric lawn mower.

Answer 507

The generation of tension during isovolumetric contraction has a high energy cost, yet accomplishes no external work. Myocardial oxygen consumption is in fact dominated by internal work rather than external work, and correlated better with active tension multiplied by the time for which it is maintained (the tension-time index) than with stroke work.

Answer 508

During dynamic exercise the gross efficiency can improve to around 15% because stroke volume increases relatively more than arterial pressure, producing more external work without much increase in the energy-expensive isovolumetric phase. This is an important point in relation to patients with cardiac disease, allowing them to indulge in gentle exercise such as waling.

Answer 509

Cardiac efficiency during exercise, emotional stress and cardiac dilatation: The opposite side of the count, however, is that a high blood pressure, whether acute or chronic, raises myocardial oxygen demand and reduces efficiency.An angry emotion scene, which causes a large rise in blood pressure, will raise the tension-time index and increase myocardial oxygen demand sharply --the very thing to be avoided by patiens with coronary artery insufficiency.

Answer 510

Laplace's law (P = 2Sw/r) shows that in order to maintain a normal systolic pressure, P, a heart of enlarged radius, r, has to exert a greater contractile force , Sw. This entails a rise in oxygen consumption and a fall in efficiency ---the very things a failing heart can least afford. Excessive cardiac dilatation is thus dangerous in heart failure, and it is important to reduce the dilatation by diuretic therapy.

Answer 511

Myocardial metabolism is normally aerobic. The immediate energy source for the actin-myocin machinery is ATP, which is synthesized by oxidative phosphorylation in the abundant mitochondria. The small store of ATP is backed up by a bigger reserve of high-energy phosphate bonds in the form of creatine phosphate. There is also a small store of oxygen as oxygmyoglobin.

Answer 512

Even so, the supply of oxygen by coronary vessels must keep pace with demand because the heart, unlike skeletal muscle, cannot stop for a rest. At basal outputs, myocardial oxygen consumption is approximately 10 ml/min per 100 g. This represents a high proportion of the oxygen delivery by the coronary blood, and about 65-75% of the coronary blood oxygen is normally extracted. The additional oxygen needed at increased work loads is obtained chiefly by increasing the coronary blood flow.

Answer 513

The metabolic substrates of myocardium: It appears that myocardium is something of an opportunist, increasing its utilization of whatever substrate is currently most abundant in the bloodstream, for example glucose after a carbohydrate meal or ketone bodies in uncontrolled diabetes. Generally, however, free fatty acids supply 65-70% of the energy requirement (or more during endurance exercise) and the remaining 30-35% is supplied roughly equally by glucose and lactate.

Answer 514

Myocardium, unlike skeletal muscle, can oxidize lactate, and this is a useful asset during hard exercise when blood lactate rises at the same time as myocardial energy demand.

Answer 515

If myocardium becomes hypoxic, however, there is a switch to the anaerobic production of lactate, leading to local acidosis and impaired contractility.

Answer 516

The oxidation of lactate involves lactic dehydrogenase of a type specific to heart (LDH-H4). When heart muscle dies after a coronary thrombosis, LDH-H4 and other intracellular enzymesm such as creatine phophokinase and aspartate aminotransferase escape into the circulation. Their detection in plasma is a valuable diagnostic test for myocardial infarction.

Answer 517

Stroke volume is controlled primarily by filling pressure via the Frank-Starling mechanism and by myocardial contractility, which depends on the intracellular calcium level, and it is opposed by arterial pressure. Both the heart rate and contractility are regulated primarily by autonomic nerves, but an increase in output normally required a coordinated change not only in cardiac nerve activity but also in peripheral resistance and the factors governing CVP.

Answer 518

laminar flow, turbulent flow, and single-file flow.

Answer 519

normal arteries, arterioles, venules and veins.

Answer 520

in the ventricles

Answer 521

In capillaries

Answer 522

The diameter of mammalian capillaries is less than the width of the human red cell.

Answer 523

The wire cooling rate being proportional to fluid velocity.

Answer 524

Flow in the vena cava increases during inspiration because the fall in intrathoracic pressure expands the intrathoracic veins.

Answer 525

The simplest guide to such hydraulic issues is Darcy's law of flow, which is the hydraulic equivalent of Ohm's law of electricity.

Answer 526

Q = K (P1 - P2) = (P1 - P2)/R where K is a proportionality coefficient called hydraulic conductance. The reciprocal of hydraulic conductance is hydraulic resistance R, and the resistance arises from internal friction within the moving liquid.

Answer 527

For the systemic circulation, flow equals cardiac output (CO), the driving pressure is mean arterial pressure minus central venous pressure (Pa-CVP), and the resistance is the total peripheral resistance (TPR). Therefore we can write Darcy's law in the form: CO = (Pa-CVP)/TPR

Answer 528

Since CVP is nearly zero (atmospheric pressure) the expression can be simplified to CO = Pa/TPR, or alternative Pa = CO x TRP

Answer 529

Providing that active changes in peripheral resistance are blocked pharmacologically, the arterial pressure is virtually a linear function of the flow, and the extrapolated line passes close to the origin.

Answer 530

The slope of the pressure-flow plot represents the systemic peripheral resistance, which is typically approximately 1 mmHg per ml/s in human adults

Answer 531

Darcy's law concerns volume flow, the units of which are volume/time, and this must be clearly distinguished from fluid velocity (distance/time)

Answer 532

The mean velocity of the fluid is its flow divided by the total cross-sectional area of the channels. Since the latter increases as blood enters the branching microvascular network, velocity decreases progressively (see Fig 1.6), whereas the total flow is unaltered and equals the cardiac output.

Answer 533

Pressure, with which Darcy's law is concerned, is only one of three sources of mechanical energy affecting blood flow; the other 2 are potential energy and kinetic energy.

Answer 534

states that flow between point A and point B in the steady state is proportional to the difference in the fluid's mechanical energy between A and B, mechanical energy being the sum of pressure energy, potential energy and kinetic energy.

Answer 535

pressure x volume (PV)

Answer 536

fluid mass x height (h) x gravitational force (g) of which fluid mass = (density p x volume V))

Answer 537

The energy that a moving mass possesses due to its momentum. Kinetic energy increases in proportion to velocity squared (V2) se formel 7.2

Answer 538

Flows occurs down a gradient of total energy rather than pressure alone.

Answer 539

In the upright posture the aortic blood possesses more gravitational potential energy than blood in the foot, in fact about 90 mmHg more, so that the total energy of aortic blood is 185 mmHg relative to the fot, and there is in fact a net energy gradient of 5 mmHg driving flow from the aorta into the foot.

Answer 540

Kinetic energy forms only approximately 1 % of the fluid energy in the aorta at rest, and 5 % in the pulmonary artery, rising to 14% and 50% respectively at maximal cardiac output. In the great veins, the kinetic energy forms a greater proportion of the fluid energy because the blood velocity is similar to that in the aorta while blood pressure is musch lower: kinetic energy account for 12% of the fluid energy in the vena cava at rest and for most of it at maximal flows..

Answer 541

On reaching the relaxed ventricle, the returning blood's kinetic energy falls virtually to zero, so there is a kinetic energy gradient from vein to ventricle which aids ventricular filling. Put another way, the momentum of the returning blood contributes to ventricular expansion.

Answer 542

It should be noted that the above laws describe flow that does not vary with time. If flow is pulsatile, as in arteries, the laws can still be applied to the mean flow, if this is not varying with time. To describe an oscillating flow instant by instant, however, is a more complex matter.

Answer 543

Nature of flow in blood vessels: | See Fig 7.2

Answer 544

Laminar flow along a cylindrical tube: In laminar flow, the liquid follows smooth, regular streamlines. If the flow is along a cylindrical tube, the liquid behaves like a set of thin concentric shells (the laminae), which slide past each other during flow. The lamina in direct contract with the vessel wall is fixed there by molecular cohesive forces (the "zero-slip" condition) and has zero velocity. The adjacent lamina slides slowly past the non-slip lamina. The next (third) lamina slides past the second lamina, and since the second lamina is itself moving, the third lamina has a higher velocity relative to the tube wall, and so on until maximum velocity is reached at the centre of the tube.

Answer 545

The high velocity of red cells in the central stream and the slow velocity of marginal red cells are plainly visible when a small blood vessel in vivo is viewed through a microscope.

Answer 546

For a simple fluid like water, the transverse velocity profile is a parabola during fully developed laminar flow (see Fig 7.2). It takes some distance form the tube entrance, however, to establish the parabola, several tube diameters in fact. In the entrance region itself, the velocity profile is almost flat, i.e. a broad core of fluid flows at almost uniform velocity. This situation exists in the aschending aorta and the near uniform velocity here facilitates the estimation of aortic flow by the Doppler method. (section 5.3)

Answer 547

With a particulate suspension like blood, the velocity profile is more blunted than a parabola (Fig 7.2), red line). Also the shearing of lamina against lamina causes the red cells to tend to orientate parallel to the direction of flow at high shear rates.

Answer 548

Shear rate is an important factor in haemodynamics: it is the change in fluid velocity per unit distance across the tube, i.e. the slope of the velocity profile in Fig 7.2.a

Answer 549

Another effect of shear in that the cells are displaced a little towards the central axis (axial flow), leaving a thin cell-deficient layer of plasma at the margins. The marginal layer is only 2-4 um thick, but it is important in arterioles, where it helps to ease the blood along (section 7.5).

Answer 550

Turbulence in the circulation: If the pressure difference across a rigid tube is progressively raised, a point is reached where flow no longer rises linearly with driving pressure, as required by Darcy's law, but increases only at the square root of pressure (see Fig 7.3). This is caused by a transition from smooth laminar flow to turbulent flow, in which swirling crosscurrents dissipate part of the pressure-energy as heat.

Answer 551

For a given smoothness of tube, turbulence is encouraged by a high fluid velocity (v), large tube diameter (D) and high fluid density (p,rho); these factors increase the fluid's momentum and thereby encourage any flow distortions to persist.

Answer 552

Turbulence is discouraged by a high viscosity (n, eta) because this tends to damp out flow deviations.

Answer 553

The Reynolds number (Re) Re = (v.D.p)/n

Answer 554

The critic Reynolds number at which turbulence sets in is around 2000 for steady flow down a rigid straight uniform tube. The critical value is smaller in blood vessels because flow is pulsatile and the vessels are neither straight nor unifom. Even so, a critiacl Re is not normally reached in most vessels; for ex Re is only approximately 0,5 in arterioles.

Answer 555

Turbulence does occur in the ventricles where it helps to mix the blood and produce a uniform arterial gas content.

Answer 556

Turbulence also occurs in the human aorta during peak flow, and this sometimes creates an innocent systolic ejection murmur audible over the aortic area. (section 2.5).

Answer 557

Turbulence can also develop in leg arteries roughened by atheromatous plaques, and can cause a local bruit (murmur) audible through the stethoscope. Normal laminar flow is of course silent.

Answer 558

The diameter of mammalian capillaries (5-6 um) is less than the width of the human red cell (8 um). Red cells are therefore compelled to proceed through capillaries in single file, and to deform into folded or parachute-like configurations even to enter the vessel, a fascinating and sometimes comic spectacle when seen through the microscope.

Answer 559

Since the cell spans the full with of the tube, parabolic flow is impossible and the bolus of plasma trapped between the cells is compelled to move along at uniform velocity, albeit with some internal eddying ("bolus flow" or "plug flow").

Answer 560

By a thin film of plasma or by the endothelial glycocalyx, a surface coating of mucopolysacchariedes.

Answer 561

On the deformability of the red cell, and this is impaired in many clinical conditions. The most dramatic of these is sickle cell anaemia, where the haemoglobin is abnormal, and in hypoxic situations this causes the red cell to adopt a rigid sickle shape which reduce capillary flow, impairs tissue nutrition, and causes serious tissue damage (the sickling crisis).

Answer 562

Red cell flexibility is also impaired in spherocytosis, a condition in which many red cells are spherical rather than biconcave owing to a deficiency of spectrin, the fibrous skeleton protein coating the inner surface of normal red cell membranes. Spheres cannot fold easily and tend to burst (haemolyze) when forced through narrow channels, causing a hemolytic anaemia. The haemolysis is particularly severe as spherocytes pass through special narrow channels inside the spleen, so splenectomy is often helpful in such cases.

Answer 563

Single-file flow in capillaries: The polymorphonuclear leucocyte is rounder and much stiffer than the red cell, and it mover less freely along the micro vessels, often creating a little "traffic jam" of red cells behind it. If the leucocyte adheres to the wall, as happens in small venues during inflammation, the resistance to flow can increase markedly. This is an important factor impairing microvascular flow during inflammation, and also in ischaemia of the myocardium and severe haemorrhagic hypotension.

Answer 564

By an heated wire in the bloodstream (hot-wire anemometry), the wire cooling rate being proportional to fluid velocity.

Answer 565

Measurement of blood flow: The non-invasive method, (described in section 5.3) is used to assess femoral artery blood flow in patients with ischaemic limb disease, and to assess placental blood flow in late pregnancy. A variant, the laser-Doppler flowmeter, uses a laser light beam rather than ultrasound and is providing useful for estimating superficial skin blood flow.

Answer 566

The Fick principle can be used to measure blood flow in several other organs besides the lungs.. The principle has been used to determine coronary and cerebal blood flow from the uptake of inhaled nitrous oxide gas from blood into these organs.

Answer 567

To measure blood flow in a limb, foot or digit. To measure forearm blood flow, an inflatable cuff is placed over the brachialveing and inflated quickly to 40 mmHg. This arrests the venous drainage but not the arterial inflow, so the forearm begins to swell with blood.The initial swelling rate equals arterial blood flow. The swelling rate is measured by a mercury-in-rubber strain gauge, Fig 7.4

Answer 568

Arterial pressure oscillates and the size of the oscillation, or "pulse pressure" depends on the volume and speed of the ventricular ejection, the rate of runoff through the peripheral resistance vessels, and the distensibility of the artery wall (see section 5.4)

Answer 569

As ventricular ejection begins, input into the arterial system is much faster than runoff and arterial volume increases even though 20-33% of the ejected blood flows away through the peripheral resistance during this phase.

Answer 570

The arterial pressure rises steeply, forming the "anacrotic limb" of the pulse. (See fig 7.6). Pressure reaches its maximum when the declining ejection rate transiently equals the runoff through the resistance vessels- Pressure then declines as ventricular systole weakness and runoff exceeds ejection rate.

Answer 571

A notch on the descending limb (dicrotic notch) marks aortic valve closure, and as the valve cusps check the backflow they create a small secondary rise in pressure, the "dicrotic wave". As runoff continues, pressure gradually declines to the diastolic value.

Answer 572

If the aortic valve is narrowed by fibrous (aortic stenosis), arterial pressure rises more sluggishly than normal during ejection and has an abnormal plateau (see Fig 7.6, inlet).

Answer 573

In aortic incompetence, pressure decays abnormally quickly in diastole owing to reflux into the ventricle. As a result, pulse pressure may be twice as big as normal, and may even cause relaxed limbs to jerk in time with the throbbing pulse.

Answer 574

Because the blood spends relatively longer near the diastolic level than near systolic levels.

Answer 575

An easier, working approximation, however, is to add a third of the pulse pressure to diastolic pressure. (se formel 7.4 s 114) mean Pa= P diast + (P sys - P diast)/3 This approximation is valid for the brachial artery waveform, where human pressure is normally measured.

Answer 576

If for ex brachial pressure is 110/80 mmHg, the pulse pressure is 30 mmHg and the mean pressure is 90 mmHg

Answer 577

MAP = CO x TPR This important expression, the mean blood pressure equation, shows that mean arterial pressure is set by the size of the cardiac output and the total peripheral resistance

Answer 578

pgh (fluid density (p) x force of gravity g x h)

Answer 579

Since mercury is very dense (p = 13.6 g/ml), a column about 100 mm high suffices to balance blood pressure. Using his new mercury manometer, Poiseuille proved that there is little change in mean pressure along the arterial system, and therefore little resistance to flow along arteries.

Answer 580

Owing to the inertia of the mercury. To record the pressure waveform, a fast-responding electronic pressure transducer is needed. The transducer contains a metal diaphragm which deforms slightly when subjected to arterial pressure via a linking catheter. The deformation of the diaphragm alters the resistance of a wire connected to it and the resistance is recorded. This produces a very fast response to pressure, but the transducer still has to be calibrated by a fluid column. For this reason, blood pressure is normally reported in mmHg or cmH2O rather than standard international units.

Answer 581

Indirect measurement by sphygmomanometry: The mercury manometer is used in medical practice throughout the world by an indirect method called sphygmomanometry. See fig 7.7 Cuff pressure is controlled by the rubber bulb (RB) and measured by the mercury column. The cuff is inflated initially to around 180 mmHg, the applied pressure being measured by a mercury manometer. The applied pressure is transmitted through the tissues of the arm and occludes the artery. Auscultation of the brachial artery at the antecubital fossa (inner aspect of elbow) with a stethoscope therefore reveals no sound at this stage. Cuff pressure is then gradually lowered, and a sequence of sounds is heard (just below systolic pressure and diminish when cuff pressure is close to diastolic pressure.

Answer 582

When cuff pressure is just below systolic pressure, the artery opens briefly during each systole. The transient spurt of blood vibrates the artery wall downstream and creates a dull tapping noise called a Korotkoff sound.

Answer 583

1. The pressure at which the Korotkoff sound first appears is conventionally accepted as systolic pressure, though it is actually about 10 mmHg less than the systolic pressure measured directly.

Answer 584

2. As cuff pressure is lowered further the Korotkoff sounds grow louder, because the intermittent spurts of blood grow stronger.

Answer 585

3. When cuff pressure is close to diastolic pressure, the artery remains patent for most of the cardiac cycle and the vibration of the vessel wall abruptly diminishes. This causes a sudden diminuendo of the Korotkoff sounds, and the cuff pressure at which this happens is accepted as the diastolic pressure (though it is about 8 mmHg higher than diastolic pressure measure directly).

Answer 586

3. A faint Korotkoff sound persist after the sudden diminuendo, and complete silence is often not attained until 8-10 mmHg below the true diastolic pressure.

Answer 587

Age: Reduced compliance is due to arteriosclerosis (hardening of the arteries by fibrosis and calcinosis).

Answer 588

Mean blood pressure may either rise or fall, depending on the balance between increased cardiac output and reduced peripheral vascular resistance.

Answer 589

Exercise: In gentle dynamic exercise pressure can fall slightly, and even in heavy dynamic exercise, where CO increases fourfold or more, the mean pressure increases by only 10-40 mmhg. In heavy static exercise such as weight-lifting, and an exercise pressor reflex can elevate pressure by approximately 60 mmHg.

Answer 590

Pressure increases in arteries below heart level owing to the weight of the column of blood between the heart and artery. In a foot 115 cm below heart level, arterial pressure will increase by 115 x 1.06/13.6 cmHg (1,06 is the relative density of blood and 13.6 the relative density of mercury): this is 90 mmHg, so arterial pressure in the foot is increased to approximately 180 mmHg above atmospheric pressure.

Answer 591

Blood pressure is reduced in the arteries above heart level and is only 60 mmHg or so in the human brain during standing. Our problems are slight, though compared with the giraffe's. To ensure cerebral perfusion, the giraffe has to generate an aortic pressure of approximately 200 mmHg.

Answer 592

Gravity: indirect effect: Upon moving from lying to standing, arterial pressure at heart level changes too due to changes in CO and peripheral resistance. A transient fall in pressure (which can pro due a passing dizziness) is followed by a small but sustained reflex rise.

Answer 593

Emotion and stress: Potent pressor stimuli: anger, appehension, fear, stress and sexual excitement.: can elevate blood pressure. The pressor effect of stress is particularly harmful to human patients with ischaemic heart disease.

Answer 594

Arterial pressure fluctuates with respiration; rising by 15-20 mmHg during each inspiration.

Answer 595

The Valsalva manoevre; a forced expiration agains a closed or narrowed glottis, causes a complex sequence of pressure changes.

Answer 596

In pregnancy, blood pressure gradually falls and reaches a minimum at approximately 6 months, so in obstetrical practice a pressure of 130/90 mmHg would cause grave concern, even though it is merely close to the upper limit of normal for a non-pregnant woman.

Answer 597

Many pathological processes also alter arterial pressure, such as dehydration, hemorrhage, shock, syncope (fainting), chronic hypertension, acute heart failure and valvular lesions like aortic incompetence.

Answer 598

Flow along the aorta and major arteries is pulsatile, and virtually ceases during diastole (See Fig 7.9). This flow pattern arises from moment-to-moment changes in the pressure gradient along the arterial system.

Answer 599

Pulsatile flow in arteries: Pressure rises first in the proximal aorta, where the stroke volume is initially accommodated, so there is at first a pressure gradient from the proximal aorta to the peripheral arteries, which causes the blood already in the system to accelerate.

Answer 600

The pressure pulse then spreads along the arterial tree, taking an appreciable time to do so; in the radial artery, for example, the pressure rises about 0,1 s later than in the aorta. Consequently, there comes a period when distal pressure is transiently higher than proximal pressure (see fig 7.9) and the pressure gradient is reversed. The reversed pressure gradient does not instantly reverse the flow because the blood has acquired forward momentum by now, but it does steadily decelerate the flow.

Answer 601

Thus, flow in the major arteries first accelerates and then decelerates over the initial third of the cardiac cycle. During the next 2/3 of the cycle flow is virtually zero.

Answer 602

The instantaneous flow is not governed by Darcy's law (which, as pointed out earlier, is a steady-state expression) but is governed by Newton's second law of motion (acceleration = force/mass)

Answer 603

The period of near zero flow gradually shortens as blood enters smaller arteries, and in the smallest arteries flow becomes continuous, albeit still pulsatile.

Answer 604

Transmission of the pressure wave: If arteries had rigid walls, pressure would rise virtually instantaneously throughout the arterial system, but they do not, and the pressure wave takes a finite time to pass along the arterial tree.

Answer 605

Since blood is essentially incompressible, the blood entering the proximal aorta during ejection has to create space for itself. This is done partly by distending the proximal aorta (which raises the pressure) and partly by pushing ahead the blood previously occupying the required space. As the displace blood moves forward, it too must make space for itself, partly by distending the wall downstream (which raises the pressure there) and partly by displacing the blood ahead. This "shunting" sequence repeats itself very rapidly, along the arterial tree. The pulse is thus transmitted by a wave of wall distention (at 4-10 m/s) while the ejected blood itself advances only 20 cm (the stroke distance) in 1 s.

Answer 606

Since the wall deforms as it propagates the pulse, the transmission velocity is affected by wall stiffness: it increases as wall stiffness increases.

Answer 607

Arterial stiffness is greater at high blood pressures and in elderly subjects, so pulse transmission is faster in elderly subjects.

Answer 608

The measurement of transmission velocity, by timing the central and peripheral pulse, forms a convenient way of assessing arterial distensibility in human subjects.

Answer 609

This peaking of the wave by around 50% is attribute partly to the tapering shape and increasing stiffness of the distal arterial tree and partly to the variation in transmission velocity with wall stiffness.

Answer 610

The pulse pressure continues to increase as far as the third generation of arteries (e.g. femoral artery) but beyond this it becomes progressively damped out by the viscous properties of the blood and artery wall (see Fig 1.6). As the oscillations in pressure and flow dwindle the blood reaches the resistance vessels (arterioles).

Answer 611

The resistance to laminar flow arises exclusively from the internal friction between adjacent laminae of fluid and has nothing to do with friction between tube and fluid, which is zero because of the zero-slip condition. (see Fig 7.2) Nevertheless, resistance is greatly affected by tube geometry because the radius of the tube affects the rate of shear (sliding) of the laminae.

Answer 612

If the same flow is forced through a narrow tube and a wide tube, the velocities are greater in the narrower tube (since mean velocity equals flow/cross-sectional area), so the shear rates are higher in the narrower tube; and high shear rates produce more internal friction.

Answer 613

Poiseuille

Answer 614

Poiseuille established that the resistance (R) to the steady laminar flow of a Newtonian fluid such as water (or plasma) along a straight cylindrical tube is proportional to tube length (L) and fluid viscosity (n); and is inversely proportional to tube radius raised to the fourth power (r4): se equation 7.1a

Answer 615

Poiseuille's law s 121 equation 7.7

Answer 616

Poiseuille's law describe flow along a single tube. If several tubes are arranged in series, the overall resistance is the sum of the individual resistances.

Answer 617

However, if the tubes are connected in parallel (e.g.capillaries), the same driving pressure will obviously produce more flow, because it is now the conducting capacities of the tubes that summate.

Answer 618

If there are N tubes of equal conductance K, the net conductance is NK; and since resistance is the reciprocal of conductance, the net resistance is 1/NK

Answer 619

Armed with Poiseuille's law, we can now consider the total systemic resistance which, as explained in section 1.6, is sited chiefly in the arterioles.

Answer 620

Owing to the fourth power in Poiseille's law, resistance is equisistively sensitive to vessel radius.

Answer 621

Tube geometry; importance of arteriolar radius: The fall in radius from approximately 1 cm in the human aorta to 0.01 cm in an arteriole will in itself increase resistance 100000000 times, and this is essentially why arterioles are the main site of resistance.

Answer 622

The pressure drop per unit length of vessel is in fact 5 times greater in capillaries than arterioles but the pressure drop across the whole capillary bed, approximately 30 mmHg, is smaller than that across the arteriolar bed (40-50 mmHg) because of 1) the huge number of capillaries in parallel arrangement, 2) the shortness of capillaries (approximately 0.5 mm), and c) the occurrence of bolus flow rather than laminar flow in capillaries.

Answer 623

The radius of an arteriole is actively controlled by the smooth muscle in its wall; contraction narrows the lumen (vasoconstriction) and relaxation produces vasodilation. Owing the the fourth-power effect on resistance, active changes in radius constitute an extremely powerful mechanism for regulating both the local blood flow to a tissue and the central arterial pressure (equation 7.5).

Answer 624

A mere 16% reduction in arteriolar radius will in theory halve the blood flow to an organ (although this is somewhat mitigated by viscosity changes, described later). It is worthwhile, therefore, considering the relation between active wall tension and vessel radius a little more closely.

Answer 625

Wall mechanics during vasoconstriction and vasodilation: The radius of a vessel depend partly on the active tension exerted by vascular smooth muscle, partly on the passive elastic properties of the wall and partly on blood pressure.

Answer 626

The net tension in the wall (T) is the sum of the tension in active smooth muscle cells (Ta) and tension in passive structures like collagen and elastin networks See fig 7.12

Answer 627

The net wall tension resists the distending force exerted by the blood pressure, which is the internal pressure (P is) times the area it act on in one direction, namely 2R i x 1 for a tube of internal radius (r i) and unit length; the internal distending force is therefore 2Piri. We must also take into account the pressure outside the wall (P0) which tends to compress the vessels which a force equal to 2 Poro (nersänkt o), where ro is the outer radius of the vessel.

Answer 628

At mechanical equilibrium, the wall tension on each side of the vessel (2T) must counteract the net distending force, and since the factor 2 cancels out, this gives: T = Piri-Poro equation 7.8) This is the fundamental equation for mechanical equilibrium in any cylinder.

Answer 629

If the wall is thin relative to the radius, the internal radius and external radius are nearly equal and the expression simplifies to T = delta x P. r, a relation known as Laplace's law for a tube.

Answer 630

This simplified version tells us that the wall of a thin pressurized vessel is under tension, something we all know for our everyday experience of balloons, footballs etc. The mechanical situation in arterioles, however, is quite unlike this and is rather surprising. Because the ratio of wall thickness to internal radius is large in arterioles (up to 1.0 see Fig 1.8), the internal pressure acts upon a relatively small area while the external pressure (atmospheric) acts on a relatively large area. As a result, the compressive force (Po ro) is larger than the distending force (pi ri), and the wall is, overall, in a state of compaction or "negative" tension rather than positive tension.

Answer 631

When the smooth muscle cells contract, producing a positive tension (Ta) within themselves, this reduces the vessel's internal radius but increases the state of compression of the passive elements in the wall, and the latter opposes further reduction of radius. In this way, mechanical stability is achieved. The key point here is that without the opposing effect of the passive elastic elements, vasoconstriction would be a highly unstable process.

Answer 632

Viscosity stems from viscum, the Latin for mistletoe, because mistletoe berries contain a thick glutinous fluid. Viscosity was defined by Isaac Newton, as defectus lubricitatis or lack of slipperiness, meaning that is is a measure of the internal friction within a moving fluid, analogous to friction between 2 moving solid surfaces.

Answer 633

The ratio of shear stress to shear rate.

Answer 634

Shear stress is the shearing or sliding force applied per unit area or contact between 2 laminae (N/m2), and it depends on the axial pressure gradient.

Answer 635

Shear rate is the change in velocity per unit distance radially , so its units are (m/s), i. e s-1 Fig 7.2

Answer 636

The viscosity of water (shear stress/shear rate) is 0.001 Newton -s/m2 at 20 grader, which is usually expressed as 1 milliPascal-second or 1 centiPoise.

Answer 637

The viscosity of a fluid relative to water is easily and accurately measured with a simple capillary viscometer. The time taken for the test fluid to flow between 2 marks in a glass capillary tube is simply divided by the time taken by water under the same pressure head. With a simple fluid like water or plasma, the viscosity is independent of the tube radius or shear rate, and such a fluid is called Newtonian. While blood by contrast has anomalous, non-Newtoninan properties.

Answer 638

The viscosity of water decreases as temperature rises, falling to 0.69 mPas at body temperature (37 grader).

Answer 639

In plasma, the presence of voluminous protein molecules (albumin and globulins) raises the viscosity by 70% so the viscosity of plasma is 1.2 mPas at 37 grader.

Answer 640

In myeloma, a cancer of globulin-secreting cells, the globulin concentration and viscosity rise to pathological levels. Moreover, the globulins are themselves abnormal and some can cause red cells to agglutinate under cool conditions.

Answer 641

In cold fingers, the viscosity can increase so dramatically that perfusion is badly impaired and necrosis of the fingertips ensues.

Answer 642

The addition of red cells to plasma greatly increases the amount of internal friction during flow, so blood viscosity is dominated by haematocrit. Fig 7.13

Answer 643

Haematocrit is the red cell volume as a fraction or percentage of the blood volume. Fig 7.13.

Answer 644

Haematocrit is the red cell volume as a fraction or percentage of the blood volume. At a haematorcrit of 47%, the relative viscosity of human blood is approximately 4, as measured in a wide-bore viscometer at high shear rates. At this haematocrit, there are frequent collisions between there red cells during flow, and were it not for the great flexibility of the red cell the viscosity would be even higher.

Answer 645

If the cells are hardened by glutaraldehyde, the relative viscosity rises to 100.

Answer 646

Achieveing the optimal haematocrit for oxygen delivery is a delicate balancing act: on the one hand a high haematocrit increases the oxygen-carryng capacity of the blood but on the other is also raises viscosity, which either reduces the flow or increases arterial pressure and cardiac work. Each species has an optimal haematocrit in this respect.

Answer 647

Abnormalities of haematocrit can have serious haemodynamic effects. Polycythaemia, a raised haematocrit, can develop either as a physiological adaptation to chronic hypoxia (e.g high altitude) or as a pathological condition called polycythaemia rubra vera, in which an overproduction of red cells by the by the bone marrow raises the haematocrit as high as 70%

Answer 648

At haematocrits above 63% the red cells are so closely packed that they are deformed even at rest, doubling the viscosity and raising the resistance to flow, which in turn predisposes to cerebral thrombosis and coronary thrombosis (strokes and heart attacks).

Answer 649

Anaemia reduces viscosity and resistance, and in order to maintain blood pressure, cardiac output has to increase. If this situation is prolonged, a form of cardiac failure called high-output failure can develop. These examples illustrate the importance of the homeostasis of viscosity for normal cardiovascular functioning.

Answer 650

In capillaries, the single-file pattern of flow lowers the viscosity. In arterioles, the viscosity is reduced by the peripheral plasma stream produced by axial flow (see Fig 7.2) .

Answer 651

Since shear rates are highest peripherally, a reduction in friction at that location has a particularly marked effect on the overall viscosity. This effect declines in wider tubes because the thickness of the marginal layer becomes insignificant relative to tube radius.

Answer 652

viscosity decreases with tube diameter. Fig 7.14

Answer 653

Fig 7.14 The effective viscosity of blood in the intact circulation is approximately 2.5, implying that the functional diameter of the resistance vessels is approximately 30 um (arterioles). At diameters smaller than a blood capillary, viscosity rises again.

Answer 654

Sketches show red cell aggregation into rouleaux at low shear rates and disaggreagation at high rates.

Answer 655

The concentration of red cells in blood flowing along a narrow tube (the dynamic or tube haematocrit) is lower than the central haematocrit in the feeding and draining vessel.

Answer 656

The explanation lies in the difference between axial and marginal stream velocities. See Fig 7.2

Answer 657

Let us consider, as a simple example, arterial blood of haematocrit 50% feeding an arteriole in which the cells have twice the velocity of plasma owing to their more axial location. If the haematocrit in the parent artery and vein is to remain at 50% (which it must, since the circulation is in a steady state) equal volumes of plasma and red cells must pass through the arteriole in a given time. Since the cell velocity is twice the plasma velocity in our example, equal volume flows are only possible if the concentration of red cells in the arteriole is half that in the parent blood. This is achieved by the red cells speeding away from the plasma at the tube entrance, thinning out rather like traffic entering a fast road from a congested slip road.

Answer 658

The viscosity of blood varies not only with tube diameter but with velocity too, or more accurately with shear rate (see Fig 7.14b).

Answer 659

Shear rate is the change in fluid velocity per unit distance normal to the direction of flow.

Answer 660

At normal, physiological flows, the average shear rates are of the order 1000/s, and the viscosity is at a minimum. But at low flows the viscosity increases steeply, because low shear rates allow the red cells to adhere to each other and form aggregates; these resemble stacks of coins and are called rouleaux. This probably occurs in veins in vivo if blood flow is sluggish.

Answer 661

The conditions under which Poiseuille's law is strictly valid include a steady flow (cf. pulsatile flow in vivo) of a Newtoninan fluid (cf. blood) along a long straight vessel (cf. branched, curved and tapering vasculature) with rigid walls (cf. distensible blood vessels). So one has to be cautious in applying Poiseuille's law to the circulation.

Answer 662

1) The elasticity of the arterioles, which permits radius to increase and therefore resistance to decrease as pressure rises. 2) alterations in blood viscosity at low shear rates due to rouleaux formation.

Answer 663

The major role played by the anomalous viscous behavior of blood becomes clear upon perfusing a dog's hindlimb with saline: a more linear pressure-flow relation is obtained, extrapolating virally through the origin. See fig 7.15.

Answer 664

In circulations with good arteriolar tone, a curious and physiologically important pressure-flow relation exists, called an auto regulation curve. Flow increases with pressure up to a certain point, but the slope of the relation then flattens and thereafter flow changes relatively little with pressure, until pressure exceeds about 180 mmHg.

Answer 665

A nearly constant flow in the face of a rising pressure indicates that resistance is rising in proportion to the pressure. This phenomenon, called autoregulation, is caused by active vasoconstriction.

Answer 666

Autoregurlation occurs in most organs except for the lung.

Answer 667

Peripheral venules and veins are thin-walled, voluminous vessel which contain roughly 2/3 of the circulating blood. They act as a variable reservoir of blood for the thoracic compartment and thereby influence the cardiac filling pressure.

Answer 668

The volume of blood in a peripheral vein depends on the venous blood pressure and on active wall tension, as illustrated in Fig 7.16

Answer 669

Because the thin-walled vein deforms easily.

Answer 670

At a transmural pressure of 1 mmHg, the vein is almost collapsed and has a narrow elliptical profile. As pressure rises towards 10 mmHg, the elliptical profile becomes progressively rounder, enabling the vein to accommodate large volume changes with just a few mmHg change in pressure. The maximum distensibility, which occurs at approximately 4 mmHg, is estimated to be approximately 100 ml/mmHg for the human venous system: over 50 times greater than the compliance of the arterial system

Answer 671

Below zero transmural pressure, the vein collapses into a dumbbell shape and any flow is confined to the marginal channels. Above 10-15 mmHg the profile is fully circular and since the stretched collagen in the wall is relatively inextensible the volume is less sensitive to pressures over 15 mmHg.

Answer 672

Other factors influencing venous volume: Degree of active tension in the smooth muscle of the venous tunica media. In the gastrointestinal, hepatic, renal and cutaneous circulations, the vein wall is innervated by sympathetic vasomotor nerves.

Answer 673

Sympathetically-excited venoconstriction reduces the capacity of these peripheral veins (see Fig 7.16, lower curve) and displaces blood into the thoracic compartment. This provides an important mechanism by which the nervous system can regulate the filling pressure of the heart.

Answer 674

Blood enters the venues at a pressure of approximately 12-20 mmHg and by the time it reaches named veins like the femoral vein, pressure has fallen to approximately 8-10 mmHg. The subsequent venous resistance is very small (except in collapsed vessels) so the 8-10 mmHg pressure head suffices to drive the cardiac output from the periphery into the central veins and right ventricle, where the diastolic pressure is 0-6 mmHg.

Answer 675

In intensive care units, CVP is often monitored directly via a catheter advances into the subclavian vein or superior vena cava. In the routine clinical examination of the cardiovascular system, however, the CVP is assessed indirectly by inspection of the neck veins. Fig 7.17

Answer 676

The external jugular ven runs over the sternomastoid muscle and the internal jugular vein runs deep to it.

Answer 677

From the venous pressure-volume curve, we know that transmural pressure is zero at the point of collapse of a vein. CVP equals the pressure at the point of collapse (zero) plus the pressure exerted by the vertical column of blood between this point and the right atrium.

Answer 678

If, for example, the point of collapse (zero pressure) is 7 cm vertical distance above the RA midpoint, CVP is 7 cm of blood (7.4 cmH2O).

Answer 679

Humans: The position of the atrium cannot of course be observed directly, but from anatomical studies it is known that the RA midpoint is approximately 5 cm lower than the manubriosternal angle, which is readily located. Thus by measuring the vertical distance between the point of collapse and the manubriosternal angle, and adding 5 cm, CVP can be stimated. Although the accuracy is only of the order +/- 2 cm, this is sufficient to detect the grossly elevated CVP which characterizes right ventricular failure. Fig 7.17

Answer 680

Humans: The normal subject has to be semi-supine because in the upright position the point of collapse is hidden below the clavicle; in RV failure by contrast the CVP may be so high that the venous pulse is visible in the neck even when the patient is upright. Fig 7.17

Answer 681

The adoption of a standing position (orthostasis) increases the pressure in any blood vessel below heart level and reduces it in any vessel above heart level because gravity is then pulling on a vertical column of fluid between the heart and the vessel. This is particularly important in veins because their volume is so sensitive to transmural pressure.

Answer 682

The weight of this fluid column raises venous pressure in the feet tenfold, from approximately 10 mmHg supine to nearly 100 mmHg upright. Fig 7.18 and 7.21 There is no counterbalancing rise in extramural pressure (unless the subject is immersed in water), so the veins distend: this is plainly visible in one's own hand on lowering it below heart level.

Answer 683

In a human adult, about 500 ml of extra blood accumulate over approximately 45 s in the distended veins of the lower limbs. This is usually called venous pooling, but the phrase is misleading in that a pool is static whereas the venous blood is of course flowing continuously.

Answer 684

Most of the additional blood comes ultimately from the intrathoracic compartment, so the CVP falls, impairing stroke volume by the Frank-Starling mechanism and provoking a transitory arterial hypotension and, sometimes, dizziness (postural hypotension). A hand count amongst medical student indicates that most healthy individuals occasionally experience this orthostatic dizziness, especially when warm and venodilated.

Answer 685

Most of the additional blood comes ultimately from the intrathoracic compartment, so the CVP falls, impairing stroke volume by the Frank-Starling mechanism and provoking a transitory arterial hypotension and, sometimes, dizziness (postural hypotension). A hand count amongst medical student indicates that most healthy individuals occasionally experience this orthostatic dizziness, especially when warm and venodilated.

Answer 686

The circulation through the limb or brain in fact resembles flow through a U-tube syphon, and flow through a rigid syphon is the same whether it is vertical, horizontal or upside down. See Fig 7.19 Indeed, if blood vessels were completely rigid, gravity would have no overall effect on the circulation.

Answer 687

No, it is because: 1) The orthostatically-induced fall in cardiac volume and output elicits a reflex increase in vasoconstrictor nerve activity to limb arterioles, and 2) there is also a local arteriolar constriction in response to the rise in local transmural pressure.

Answer 688

In vessels above heart level, the effect of gravity is to reduce blood pressure, and when the transmural pressure falls to zero or less, the unsupported superficial veins collapse. Deeper veins are better supported and do not collapse completely.

Answer 689

Because gravity reduces the pressure of the cerebrospinal fluid around them too, so the transmural pressure hardly changes.

Answer 690

cerebral hypoperfusion. To prevent this, an anti-gravity suit is worn; bags inflate automatically around the legs to raise extramural pressure and minimize venous dissension during turns.

Answer 691

This distends the retinal vessels and causes a "readout" of vision.

Answer 692

In space travel, the circulation is subjected to zero gravity for long periods, but as this is not dissimilar to a supine posture or to floating in water, it presents no special problem for the cardiovascular system until the return to positive gravity.

Answer 693

Pressure is pulsatile in veins close to the RA, such as the jugular veins. The pulse pressure is a few mmHg, just sufficient to move the overlying skin and render itself visible but too small to be palpable, unlike the arterial pulse.

Answer 694

Waveform of venous pulse: see section 2.3. Fig 7.2: pressure waves to the oscillations in venous flow.

Answer 695

because the ballistic effect of firing out a mass of blood propels the ventricle downwards (Newtons's law of action and reaction), stretching the atrial and helping to suck blood into them. This second spurt is boosted by the elastic recoil of the ventricular walls when end-systolic volume is low (e.g. exercise)

Answer 696

Thus flow through the great veins, whilst primarily driven by the upstream pressure of about 8 mmHg (pressure from behind), is aided by 2 transient reduction in downstream pressure due to the motion of the heart (suction from in front).

Answer 697

Venous flow can also be assisted by 2 non-cardiac factors; the skeletal muscle pump and the effect of breathing.

Answer 698

When a skeletal muscle contracts it compresses the veins within, expelling their blood into the central veins. Venous valves prevent retrograde flow and ensure that the emptied segment refill from the periphery during muscle relaxation.

Answer 699

1) The pump redistributes venous blood from the periphery into the central veins, and this prevents CVP from falling during exercise. Fig 6.11 The muscle pump may ven increase CVP slightly and move the ventricle up the Starling curve.

Answer 700

2) Like any pump, the muscle pump lowers pressure in the feed line: Distal venous pressure falls because as the muscle relaxes blood drains rapidly from the distal veins into the empty muscle veins. At the same time, closure of the proximal valves interrupts the vertical column of blood between limb and heart. This reduces venous pressure in the foot and calf from around 90-100 mmHg in immobile orthostasis to 20-40 mmHg during walking, running, cycling etc As a result, the arteriovenous pressure difference driving blood flow through the calf muscle increases by 50-60%.

Answer 701

3) The muscle pump reduces capillary filtration in the legs too since capillary pressure is closer to venous pressure than to arterial pressure, and this reduces the tendency of a dependent limb to swell during exercise.

Answer 702

If the venous valves become incompetent, the muscle pump becomes ineffective. Since the vertical blood column can no longer be effectively broken up, the veins are subjected to a chronically-rasied pressure load, which leads to permanent distension. In addition, the distal tissues swell due to the unrelieved high capillary filtration pressure, and this can provoke throphic skin changes and ulceration.

Answer 703

increases Because the fall in intrathoracic pressure expands the intrathoracic veins. At the same time, the diaphragm compresses the abdominal contents, raising the abdominal venous pressure and enhancing venous flow from abdomen to thorax.

Answer 704

Conversely, vena caval flow slow during expiration, especially during forced expiration or a Valsalva manoeuvre. Coughing for ex can elevate intrathoracic pressure to 400 mmHg, and paroxysmal coughing can impede venous inflow to such a degree that fainting results.

Answer 705

The respiration-related oscillations in venous return evoke oscillations in stroke volume. RV stroke volume rises during inspiration owing to increased RV filling. LV stroke volume on the other hand falls because the stretched pulmonary vessels have a greater capacitance and this reduces the left side filling pressure. The situation reverses during expiration, so the output of the 2 ventricles are regularly out of phase, though equal when averaged over the respiratory cycle.

Answer 706

The smallest arteries branch into first-order arterioles with muscular walls innervated by sympathetic nerves. These branch into second and third order arterioles and finally into the terminal arterioles whose walls contain smooth muscle but few vasomotor nerves, control being dominated at this level by local metabolites.

Answer 707

Continuous capillaries are found in muscle, skin, lung, fat, connective tissue, and the nervous system.

Answer 708

About a quarter of the cytoplasmic volume is occupied by vesicle of diameter 60 nm, which are thought to be involved in transporting macromolecules into the cell (endocytosis) and, more controversially, across it (transcytosis).

Answer 709

the glycocalyx | as revealed by cationic probes

Answer 710

Fenestrated capillaries are an order of magnitude more permeable to water and small hydrophilic solutes than most continuous capillaries.

Answer 711

In addition to its passive functions as a porous membrane, the capillary wall has many active metabolic functions.

Answer 712

This delivery takes place across the thin walls of capillaries, which thus subserve the ultimate function of the cardiovascular system.

Answer 713

The capillary wall is also the site of fluid exchange between plasma and interstitial fluid, and thereby influences the volume of each compartment.

Answer 714

Active metabolic functions are also being increasingly documented for endothelial cells.

Answer 715

A few tissue, such as mesentery, have a ring of smooth muscle at the capillary entrance, the pre- capillary sphincter, governing capillary perfusion but most tissues lack these.

Answer 716

Another specialized structure is the arteriovenous anastomosis: a broad muscular vessel bypassing the capillary network in the skin of the extremities (fingers, nose, ear); it is involved in temperature regulation.

Answer 717

The capillaries themselves are of microscopic size (diameter 5-8 um, capillary means hair-like).

Answer 718

The venous ends of capillaries unite to form pericytic venules (postcapillary venule) whose walls contain pericytes but no smooth muscle, these too are exchange vessels. Smooth muscle reappears in the walls of venues of 30-50 um diameter.

Answer 719

The non-uniformity within a microcirculation is striking. Capillaries vary in length (typically 500-1000 um), in blood flow, and in dynamic haematocrit even within the same tissue at the same time.

Answer 720

Blood flow waxes and wanes ever 15 s or so in some capillary modules and can stop briefly due to spontaneous rhythmic contractions in the terminal arterioles (vasomotor). This influences both solute exchange and clid exchange.

Answer 721

In well-perfused capillaries, however, the blood velocity is typically 300-1000 um/s and the transit time is 0.5-2 s; this is the time available for plasma to unload oxygen, glucose etc, and load up with carbon dioxide etc. Mean transit time can fall to approximately 0,25 s in exercise.

Answer 722

Because it determines: 1) the total area of capillary wall available for exchange between blood and tissue and 2) the intercapillary spacing and therefore the maximum blood-to -cell distance, which has a large effect on diffusion time. table 1.1

Answer 723

In the myocardium and brain, where oxygen consumption is is high and sustained, the capillary density is even greater than in skeletal muscle. In the lung, capillary area is very high indeed: ca 3500 cm2/g.

Answer 724

Structure of exchange vessels: The term embraces both sides of the anatomical capillary bed because some oxygen diffuses through the walls of terminal arterioles and some fluid crosses the walls of pericytic venues

Answer 725

continuous, fenestrated, and discontinuous (in order of increasing permeability to water).

Answer 726

Continues capillary are found in muscle, skin, lung, fat, connective tissue and the nervous system.

Answer 727

In section, the circumference is formed by one to three flattened endothelial cells resting on a basement membrane. See Fig 8.2. The wall is only one cell thick, so the diffusion distance is very small (ca 0,5 um).

Answer 728

Pericytes, or "Rouget cells" partly envelop the capillary and there is some evidence that these can contract, though the significance of this is unclear.

Answer 729

The endothelial cell contains mitochondria, endoplasmic retiuculum, a Golgi apparatus, and filaments of actin and myosin. The latter form distinct stress fibres in spleen endothelium, and splenic capillaries appear to be actively contractile.

Answer 730

Most capillaries however, are through to be non-contractile under physiological conditions, although contraction of venular endothelial cells can occur in acute inflammation. Section 9.11

Answer 731

Certain endothelial features are particularly important for solute transfer, namely the intercellular junction, vesicle system and surface coat (glycocalyx).

Answer 732

These are parallel-sided clefts whose entrance occupies 0,1-0,3% of the capillary surface. They are almost certainly the transcapillary route taken by most fluid and by metabolites like glucose.

Answer 733

In cross-section the gap is 15-20 nm wide for most of its length, and this is much wider than the diameter of a glucose molecule (0,9 nm) or even albumin (7,1 nm).

Answer 734

At one to 3 points along the cleft, the adjacent cell membranes touch and form "tight junctions", but the junctions do not provide a continuous seal around the cell perimeter.

Answer 735

junctional strands See Fig 8.3 These run round the cell perimeter but are interrupted by 2 kinds of break. 1) gaps of 5-11 nm occur between individual particles, and probably account for the open junctions occasionally seen in transverse sections. 2) The junctional strands sometimes come to an abrupt end leaving a tortuous but open route through the intercellular cleft. (The overlap of other strands prevents this tortuous bypass from being seen in a single transverse section but serial transverse sections confirm its existence).

Answer 736

In pericytic venules, which are actually more permeable than capillaries, the overlap of the junctional strands is less marked.

Answer 737

In brain capillaries, which have a very low permeability to fluid, the strands are numerous and complex and extend without interruption around the perimeter to form a true seal (zonula occludes), as in tight epithelia.

Answer 738

About a quarter of the cytoplasmic volume is occupied by vesicles of diameter 60 nm, which are thought to be involved in transporting macromolecules into the cell (endocytosis) and, more controversially, across it (transcytosis).

Answer 739

Some vesicles open directly onto the cell surface by a stalk 20 nm wide while others look as though they are floating free in the cytoplasm. This led to the idea that vesicles might ferry plasma proteins across the cell, loading up at the surface, detaching and diffusing across the cell to release their load at the abluminal side.

Answer 740

The endothelial surface is coated with a thin layer of negatively-charged material called the glycocalyx, as revealed by cationic probes (positively charged probes; see Fig 8.5).

Answer 741

The glycocalyx permeates the intercellular cleft and lines the caveoli too. It consist of a meshwork of fibrous molecules with protein cores and sugar based side chains (namely sialoglycoproteins and glycosaminoglycans such as heparin sulphate), and there is growing evidence that this meshwork may act as a macromlecular sieve in the capillary wall.

Answer 742

The basal lamina (often called basement membrane) is 50-100 nm thick and consist of a dense region (lamina densa) separated from the cell by a lighter region (lamina rara).

Answer 743

The lamina densa consists of a network of type IV collagen molecules and negatively-charged heparin sulphate proteoglycan. It is attached to the cell by a cross-shaped glycoprotein called laminin.

Answer 744

The basal lamina membrane endows the capillary with sufficient strength to withstand blood pressure, but the stresses involved are actually quite small owing to the small radius of curvature (see Laplace's law: equation 7.8).

Answer 745

The basal lamina retards but does not prevent the passage of protein molecules, except in renal glomerual capillaries where a double lamina densa holds back macromolecules such as ferritin.

Answer 746

Renal glomerulus and tubules, exocrine glands, intestinal mucosa, ciliary body, choroid plexus, synovial lining of joints, and also in endocrine glands.

Answer 747

The endothelium is perforated by small circular windows, the fenestrae (diameter 50-60 nm), which allows plasma within 0,1 um of the extra vascular space.

Answer 748

Fenestrae are the major route by which water and metabolites cross fenestrated capillaries. The fenestrae are mostly not open holes but are bridged by an extremely thin membrane, the fenestral diaphragm (thickness 4-5 nm), which is sandwiched between the glycocalyx and basement membrane.

Answer 749

As a result, these capillaries are permeable even to plasma proteins. They occur wherever red cells need to migrate between blood and tissue, i.e. bone marrow, spleen and liver.

Answer 750

The passage of water and solutes across the capillary wall is a passive process requiring no energy expenditure by the endothelium.

Answer 751

Fluid movement across the wall is a process of hydraulic flow down pressure gradients set up by the heart.

Answer 752

Water molecules also diffuse extremely rapidly across the wall but this diffusion is bidirectional an no net transport results.

Answer 753

Metabolite exchange is mainly a process of passive diffusion down concentration gradients set up by tissue metabolism. To a minor extent, metabolits are also swept along in the transcapillary stream of fluid (convective transport), but the stream is relatively slow and can often be neglected.

Answer 754

Macromolecules diffuse more slowly than metabolites like glucose, so convective transport across the capillary wall is relatively more important in their transport.

Answer 755

Diffusion, and not fluid filtration, is the dominant transcapillary trasport for glucose and other small solutes.

Answer 756

To understand capillary exchange, we must consider the nature of diffusion and convection across a porous membrane and equip ourselves with a basic kit of simple transport expressions.

Answer 757

the rate of diffusion, i.e, the mass of solute transferred by diffusion per unit time (Js). See Fig 8.6a.

Answer 758

Diffusion rate depends on the concentration difference driving diffusion (delta C), the distance across which diffusion is occurring (Delta x) , the ration delta C/delta C being the concentration gradient, surface area (S), and the diffusion coefficient (D), which represents the intrinsic velocity of the solute. Js = - DS x delta C/delta x (8.1 ses 143)

Answer 759

The negative sign indicates that solute flux occurs down the concentration gradient. The diffusion coefficient (D) depends on temperature, solvent viscosity and solute size.

Answer 760

For most solutes, D is inversely proportional to the cube root of the molecular weight, so small molecules diffuse faster than big ones.

Answer 761

The diffusion coefficient is often used to calculate the radius of the molecule, idealized as a sphere (the Stokes-Einstein radius or diffusion radius- See Table 8.1 and appendix.

Answer 762

Diffusion through a large volume of solvent is called free diffusion. When a solute diffuses across a membrane, however, several factors slow the diffusional process.

Answer 763

If the solute is confined to solvent-filled pores penetrating the membrane, the area available for diffusion is reduced from the total surface (S) to the pore area (A). See Fig 8.6b

Answer 764

Moreover, for a molecule of radius a, the centre of the molecule can get no closer to the pore rim than distance a, so only a fraction of the pore space is available to the molecule. If the pore happens to be cylinder of radius r, the available fraction is (r-a) upphöjt i 2/ r upphöjt i2. See Fig 8.7. This geometrical effect is called steric exclusion.

Answer 765

Owing to steric exclusion, the concentration of solute in pore water is less than the concentration in bulk solution, and the ratio of the 2 concentrations at equilibrium is called the equilibrium partition coefficient Ø (phi). For a neutral cylindrical pore Ø equals the fractional space (r-a) upphöjt i 2 /r uppjöjt i 2. Thus steric exclusion reduced the pore area available for diffusion to Ap x Ø

Answer 766

If the pores run obliquely through the membrane, as endothelial junctions mostly do, the diffusion distance is greater than the membrane thickness as illustrated in Fig 8.6b.

Answer 767

Intrapole diffusion: Whenever a solute moves through water it experiences frictional resistance, called hydrodynamic drag; this is what governs the diffusion coefficient.

Answer 768

The hydrodynamic drag on a solute inside a pore rises progressively as the solute radius approaches pore radius in size, because the water slips less easily past the solute molecule in the confined space of a pore. As a result, the solute diffusion coefficient within the pore (D) is smaller than its free diffusion coefficient in bulk solution (D; restricted diffusion). The restriction to diffusion increases rapidly when solute/pore size exceeds one-tenth; for example, the restricted diffusion coefficient is half the free value when solute radius is 15% of pore radius.

Answer 769

As a result, the solute diffusion coefficient within the pore (D) is smaller than its free diffusion coefficient in bulk solution (D; restricted diffusion). The restriction to diffusion increases rapidly when solute/pore size exceeds one-tenth; for example, the restricted diffusion coefficient is half the free value when solute radius is 15% of pore radius.

Answer 770

Because of the above effects, Fick's law is modified by the presence of a membrane. See 8.2 s 144.

Answer 771

Js = -P S delta C

Answer 772

The permeability is governed by the restricted diffusion coefficient D, the pore length (delta x) and the fractional pore area available to the solute. The study of capillary permeability therefore has the potential to reveal a great deal about the porosity of the capillary wall.

Answer 773

The pressure gradients and on the hydraulic conductance of the membrane. The latter is defined as the filtration rate (Jv), produced by unit pressure difference acting across unit area of membrane.

Answer 774

Hydraulic conductance, like the other properties considered above, depends on the porosity of the membrane.

Answer 775

The reflection coefficient influences not only osmotic pressure but also solute transport by convection (wash along or solvent drag) because only the fraction of solute that is not reflected can be washed into a pore. The rate at which solute is dragged across a porous membran by solvent thus depends on the solvent flow, the concentration of solute, and the admitted fraction.

Answer 776

1) The rate of solute transfer 2) The membrane area 3) The concentration difference across the wall

Answer 777

With slowly exchanging solute alike albumin, the difference between arterial and venous concentrations is small and unreliable, but net transfer by all processes (diffusion, convection and vesicles) can be calculated as prenodal lymph flow x concentration in lymph.

Answer 778

Because perfusion of some capillaries is only intermit tents in certain organs.

Answer 779

Because the average plasma concentration is not simply the arithmetic average of venous and arterial concentrations. This arises from the fact that the concentration falls non-linearly along a capillary; declining most steeply at the inlet where the transmural concentration gradient and therefore efflux is highest. See Fig 8-10

Answer 780

The second main factor affecting permeation is the solute's molecular size, and capillary permeability to glucose is nearly 1000 times greater than to albumin.

Answer 781

1. Lipid-soluble molecules 2. Small lipid-insoluble molecules 3. Large lipid insoluble molecules (macromolecules)

Answer 782

Virtually the entire capillary surface is therefore available for diffusion, and this explains the high permeability.

Answer 783

The oil:water partition coefficient is ca 5 for oxygen and 1.6 for CO2, so capillaries are extremely permeable to respiratory gases; indeed, the permeability to oxygen is so high that some gas exchange even occurs in arterioles, and the haemoglobin saturation can fall to ca 80% even before the blood enters the true capillaries. Anaestetic agents and the flow-tracer xenon also falls into this class of solute.

Answer 784

via paracellular water-filled channels. The existence of these channels explains why the permeability of capillaries to water and small lipid-insoluble molecules is 2-3 orders of magnitudes higher than the permeability of most cell membranes.

Answer 785

Another way of estimating the size of the small pores is to measure the reflection coefficient.

Answer 786

Difference in permeability due to differences in pore density: The permeability of capillaries to small lipophobic solutes like potassium and sodium ions varies very widely for different organs; the permeability of frog mesenteric capillaries and salivary gland capillaries, for ex, is over ten times larger than the permeability of muscle capillaries.

Answer 787

solute permeability.

Answer 788

It thus appears that channel width is the same in capillaries with a high or low permeability; the physiological variation in permeability between organs with continuous or fenestrated capillaries is not due to differences in pore size but is due to differences in the total ara of the wall occupied by pores and/or the pore length.

Answer 789

by recording the extravascular accumulation of radio labeled albumin after an intravascular injection or by collecting and analyzing pre nodal lymph.

Answer 790

20-70% This should not be thought of as some lamentable "leak", on the contrary, it is a functional necessity, both for interstitial defense by immunoglobulins and for the transfer of protein-bound substances like iron, copper, vit A, lipids, thyroxine, testosterone and oestradiol.

Answer 791

The permeably versus molecular size plot again: Permeability declines steeply as solute radius approaches 3.5 nm (albumin) because the solute radius is approaching the width of the equivalent small pores. beyond this point, however, the permeability-size plot change slop, and the permeability to larger macromolecule declines only slightly more than one would except from the decline in free diffusion coefficient.

Answer 792

Calculations suggest that there is typically around 1 large pore per 12000 small pores. As regards fluid transport, it is estimated that at a normal filtration rate, 73-94% of the fluid passes through the small pore system, and only 6-27% through the large pores in dog hindpaws and cat intestine.

Answer 793

In the discontinuous capillaries of liver, however, the large:small pore ratio is higher, approximately 1:100. Conversely, rengal glomerular capillaries and cerebral capillaries may lack a large pore system entirely.

Answer 794

Diffusion, convection and vesicular transport

Answer 795

A rise in filtration rate is known to increase the rate of transport of macromolecules across the capillary wall many fold; so convective transport (solvent drag) through hydraulically continuous large pores clearly dominates protein transport at moderate to high filtration rates, but diffusion or vesicular transport might become relatively more important at low filtration rates.

Answer 796

Large proteins like fibrinogen undergo more reflection by the capillary wall than do smaller proteins like albumin, so the larger plasma proteins are less abundant in interstitial fluid. This process is called molecular sieving.

Answer 797

Its charge, as well as size.

Answer 798

Repulsion of the molecule by the fixed negative charges of the glycocalyx and basement membrane. The charge effects is most marked for the smaller macromolecules which are known to pass partly through the small pores, so the effect probably arises mainly in the small pores.

Answer 799

Anatomical location of the small pores: The intercellular cleft is generally regarded as the region where the small pores are located.

Answer 800

The differences in permeability between organs appear to be due principally to differences in the fraction of the cleft's surface area that is functionally open (i.e. not sealed).' In muscle capillaries, for example, only approx 10% of the intercellular cleft needs to be open to account for the wall's permeability. In cerebral capillaries less than 0,1 %, in frog mesenteric capillaries about 50%.

Answer 801

An observation which highlight the importance of the glycocalyx is the protein effect.

Answer 802

In discontinuous capillaries there are open intercellular gaps which are undoubtedly the large pores. See Fig 8.2. In healthy continuos and fenestrated capillaries the nature of the large pore is more controversial.

Answer 803

Protein transport is certainly not an active process for it is not abolished by metabolic poisons or tissue cooling.

Answer 804

Although cerebral capillaries are highly permeable to oxygen and CO2, they are exceptionally impermeable to small lipophobic molecules like K+, L-glucose, sucrose, mannitol, polar dyes, catecholamines, and plasma proteins. This gives rise to the concept of "blood-brain barrier", which protect the delicate neuronal circuits from interference by plasma solutes.

Answer 805

The blood-brain barrier is created by the dense complex junctional strands, which form a continuous seal around the endothelial cell perimeter (zonula occludes), and by the scantiness of the vesicular system.

Answer 806

Glucose in its natural dextro-rotatory form (D-glucose, dextrose). D-glucose unlike the stereo-isomer L-glucose, rapidly crosses the blood-brain barrier by facilitated diffusion.

Answer 807

D-glucose unlike the stereo-isomer L-glucose, rapidly crosses the blood-brain barrier by facilitated diffusion. It binds reversibly to a specific carrier protein in the endothelial cell membrane, and this renders the capillary wall selectively permeable to D-glucose. The movement of glucose is nevertheless a passive diffusion down the concentration gradate set up by neuronal activity, and is not an active transport.

Answer 808

The cerebral endothelium also seems capable of active ionic transport. If brain interstitial K+ concentration rises due to neuronal electrical activity, K+ is pumped out across the abluminal membrane of the endothelial cell, where a Ka+-K+ ATP ase is located (rather as in a tight epithelium). This stabilizes the level of K+ in brain interstitium and probably explains why cerebral endothelium has 5-6 times as many mitochondria as muscle endothelium.

Answer 809

Consequently, exchange involves only the initial segment of the capillary (See Fig 8.14, curve F). If flow is increased, an equilibrium may still be reached before the end of the capillary, albeit a little further downstream, and the arteriovenous concentration difference is unaltered.

Answer 810

From the Fick principle, we know that solute transfer is direct proportional to blood flow if the arteriovenous difference is constant, and this is indeed how lipid-solublelike antipyrine behave. A rise in blood-flow is thus an important way of increasing the transfer of lipid-soluble substances, like oxygen, in an active tissue.

Answer 811

Because the fraction of capillary wall involved in exchange is unknown. Instead, the solute transfer rate is a measure of blood flow.

Answer 812

By the diffusional resistance of the capillary wall.

Answer 813

Diffusion-limited exchange is relatively insensitive to blood flow because raising the blood flow reduces the time spent in the capillary: extraction falls and venous concentration rises. By applying the Fick principle, we find that the effect of the rise in blood flow is largely offset by the fall in Ca-Cv, and solute exchange increases relatively little. Fig 8.14 b

Answer 814

1. Capillary recruitment 2. Increased concentration gradient across the wall 3. Increased blood flow.

Answer 815

Capillary recruitement: In resting skeletal muscle, half to 3/4 of the capillaries are either not perfused or perfused only sluggishly at any moment, owing to vasomotion in the terminal arterioles.

Answer 816

Capillary recruitement: During exercise, the metabolic dilatation of terminal arterioles increases the number of well-perfused capillaries, and this not only increases the surface area for exchange but also reduces the diffusion distance.

Answer 817

Diffusion distance is especially important for gas exchange, because the main diffusional resistance in the overall blood-to-tissue pathway is not at the capillary wall but in the tissues, due purely and simply to the greater length of the extravascular pathway (>10um). The main fall in oxygen conc is thus not from plasma to pericapillary space but from pericapillary space to cell interior.

Answer 818

An increased cellular metabolic rate lowers the intracellular concentration of glucose, oxygen etc. and thereby increases the concentration difference between plasma and the cell. In combination with the shortened cell-to-capillary distance, this raises the concentration gradient (delta C/deltax) driving solute from the plasma to the cell.

Answer 819

Blood flow usually increases in proportion to an organs metabolic rate (See Fig 8.16), and if exchange is flow-limited (e.g.oxygen transfer), the flux into the pericapillary space increases in proportion to blood flow for a given pericapillary concentration.

Answer 820

Metabolites such as glucose and urea are flow-limited at resting blood flows but become diffusion-limited at the high flows occurring during exercise. Once the exchange process has become diffusion-limited, further rises in blood flow have only a small benefit.

Answer 821

1) it secretes structural components; the glycocalyx and basal lamina.

Answer 822

2) The endothelial cell produces several vasoactive substances, for ex, prostacyclin (PGI2), a vasodilator and anti-platelet aggregating factor. Arterial endothelium secrets endothelium-derived relaxing factors and endothelin. An endothelial surface enzyme converts circulating angiotension I into the vasoactive form angiotensin II, and degrades the circulating vasoacitve substances bradykinin and serotonin.

Answer 823

3) There is evidence that carbonic anyhydrase, an enzyme catalyzing the conversion of plasma HCO3- to carbon dioxide, occurs as another surface enzyme in lung micro vessels.

Answer 824

4). Another cluster of activity concerns the clotting system, the endothelium being a producer of thromboxane and von Willebrand factor (factor VIII-related substance).

Answer 825

Von Willebrand disease is a genetically-determined failure of endothelioid cells to synthesize the haemostactic factor, resulting in a prolonged bleeding-time

Answer 826

Endotelium is also involved in the defense against pathogens. Venular endothelium interacts with polymorphs and lymphocytes during inflammation as the first step in white cell emigration. Moreover, endothelial cells are themselves capable of actively phagocytosing bacteria, although perhaps not of killing them.

Answer 827

Impelled by the pressure within the capillaries, fluid filters slowly across the capillary wall, passes through the interstitial space and returns to the bloodstream via the lymphatic system. The entire plasma volume (except the protein) circulates in this fashion in under a day, so the maintenance of normal plasma and interstitial volume depends directly on capillary and lymphatic function.

Answer 828

Abnormalities of these vessels can give rise to inflammatory swelling and lymphoedema respectively, while abnormalities of the filtration forces give rise to other forms of clinical edema.

Answer 829

Starling's principle of fluid exchange: Fluid movement across the capillary wall is a passive process driven by the pressure on either side of the wall. Capillary blood pressure determines filtration into the tissue, and the osmotic "suction" pressure of the plasma proteins determines absorption from the tissue, as Ernst Starling realized in 1896.

Answer 830

A simple experiment led Starling to advance the hypothesis that the capillary wall is a semipermeable membrane across which plasma proteins exert an osmotic pressure.

Answer 831

Starling recognized that it is the colloid (i.e proteins) osmotic pressure that retains water within the circulation, and this discovery led to the use of colloid solutions as plasma volume expanders for the wounded in World-war I, and subsequently to the development of moderns therapeutic colloids.

Answer 832

The net rate and direction of fluid movement (Jv) depends on the net filtration pressure across the capillary wall; The net filtration pressure is the difference between the hydraulic pressure drop and colloid osmotic pressure drop across the wall.

Answer 833

The drop in hydraulic pressure is the capillary pressure (Pc) minus interstitial pressure immediately outside the wall (Pi), and the osmotic pressure difference is plasma colloid osmotic pressure (Pi p), minus the colloid osmotic pressure of interstitial fluid immediately outside the wall (Pi i)

Answer 834

Filtration rate (alpha) = Hydraulic drive-osmotic suction

Answer 835

The capillary wall is not a perfect semipermeable membrane, being slightly permeable to plasma proteins.

Answer 836

The potential osmotic pressure of a solution is not fully exerted across a leaky membrane, and the reduced osmotic pressure, expressed as a fraction of the full osmotic pressure exerted by the same concentration difference across a perfect membrane, is called the reflection coefficient (sigma).

Answer 837

For plasma proteins, sigma is typically 0,75-0.95, meaning that only 75-95% of the potential osmotic pressure difference across the wall is actually exerted. It must be stressed that this effect is not caused by the presence of protein in the interstitium.

Answer 838

The correct expression for fluid movement is the equation seen in 9.3 p 164. This final form is called the Starling equation and it is central to the understanding of clinical edema.

Answer 839

The Starling equation applies to each consecutive small segment of the capillary wall, where Pc etc can be regarded as uniform. Over the whole length of the vessel, however, the capillary pressure changes

Answer 840

1) The initial filtration rate is linearly proportional to capillary pressure and the steepness of the relation represents wall conductance.

Answer 841

Filtration rate is zero when capillary press is close to the perfusate's COP, and lowering the pressure beyond this point produces a transient absorption of interstitial fluid.

Answer 842

The capillary pressure that produces zero filtration is equal on average, to 82% of the perfusate's COP.

Answer 843

If capillary pressure is suddenly raised (usually by congesting the venous outflow and waiting several minutes for blood volume to stabilize), the early filtration rate increases linearly with pressure.

Answer 844

Conversely, if plasma COP is raised, the filtration rate decreases, in accordance with the Starling equation.

Answer 845

Care is needed, however, in applying the Starling equation to prolonged filtration states, because this may alter the interstitial pressures

Answer 846

The capillary filtration coefficient (or capacity),

Answer 847

The capillary filtration coefficient (or capacity) represents the sum of the hydraulic permeabilities of all the exchange vessels within the tissue, i.e., the sum of their surface area x conductance values.

Answer 848

The capillary filtration capacity in cat intestine, where the mucosal capillaries are fenestrated, is 20 times higher than the capacity in 100 g of human forearm.

Answer 849

The Starling principle related primarily to a short segment of capillary wall over a brief period of time, since each pressure term is the invariant. For the whole capillary bed, however, capillary pressure changes with distance along the capillary, and can also vary with time.

Answer 850

Pressure in the exchange vessels is the most variable of the 4 Starling pressures, and is the only one under nervous control. It is influenced by distance along the capillary, arterial and venous pressures, vascular resistance and gravity.

Answer 851

Axial distance: pressure falls by approximately 1.5 mmHg per 100 um length of mammalian capillary owing to the vessel's hydraulic resistance.

Answer 852

The average pressure is lower in portal circulations (hepatic sinusoids; ca 6-7 mmhg, renal tubular capillaries; ca 14 mmHg) and in the pulmonary circulation (ca 10 mmHg) than for ex in the human skin at heart level: ca 32-36 at the arterial end of the capillary to ca 12-25 mmHg at the venous end.

Answer 853

If precapillary resistance is high, the capillary is all shielded from arterial pressure: the precapillary pressure drop is great and capillary pressure is close to venular pressure. If post capillary resistance is relatively high, the situation is somewhat like a hosepipe whose outlet is squeezed: the pressure rises until it nearly equals supply pressure, namely arterial pressure. Mean capillary pressure depends on the balance between these 2 effects; i.e, on the ratio of pre-to post capillary resistance (Ra/Rv) Fig 9.4

Answer 854

The value of pre-to post capillary resistance (Ra/Rv) is typically 4 or more in systemic organs, so capillary pressure is more sensitive to venous pressure than to arterial pressure. This is why venous congestion affects filtration rate so markedly. See Fig 9.3

Answer 855

The pre-to post capillary resistance (Ra/Rv) ratio is actively controlled by central mechanisms (sympathetic vasoconstrictor nerves and circulating hormones) and by local mechanisms (myogenic response and tissue metabolites).

Answer 856

Both arterial and venous pressures increase linearly with vertical distance below heart level, reaching 180 mmHg and 90 mmHg respectively in the feet of a standing man of average height. Capillary pressure inevitably increase too, but does so by a smaller amount than either the arterial and venous pressure, because local vasoconstriction raises Ra/Rv to 20-30 and sifts the capillary pressure very close to the lower venous limit of its range.

Answer 857

The mechanisms of the local vasoconstriction may be partly myogenic and partly a local axon reflex involving sympathetic nerve terminals. Even so, capillary pressure reaches approximately 95 mmHg in the motionless dependent foot and exceeds plasma COP thouthout most of the lower body in the upright position.

Answer 858

The process of osmosis across a semipermeable membrane is illustrated in Fig 9.5

Answer 859

depends on the number of particles in solution but not on their chemical identity.

Answer 860

Plasma contains about 0,3 moles per particle per litre, mostly in the form of sodium, chloride and bicarbonate ions. However, this potential osmotic pressure is simply not exerted across the capillary wall because 1) high permeability of the small pore system to electrolytes (except in the brain) quickly establishes an electrolyte equilibrium between plasma and interstitium, and 2) the average reflection coefficient of the capillary wall to electrolytes is only approximately 0,1. Thus it is only the plasma proteins, at a concentration of merely 0,001 moles/litre, that exert a sustained osmotic pressure across the capillary wall.

Answer 861

Plasma COP is 20 mmHg in the dog (ca 60-75 g protein/litre).

Answer 862

Albumin comprises only half of the plasma protein by weight, but is responsible for 2/3 to 3/4 of the plasma COP because its molecular weight (69000) is half that of gamma globulins (150 000) and hence its molar concentration is higher.

Answer 863

Plasma COP thus depends on the albumin:globulin ratio as well as total protein concentration.

Answer 864

liver See Fig 9.6

Answer 865

Over half the plasma protein mass in the body is actually in the interstitial compartment (16% BW) rather than in the smaller plasma compartment (4% BW).

Answer 866

The whole-body average interstitial concentration plasma protein is estimated to be 20-30 g/litre, corresponding to a COP of 5-8 mmHg, but the value varies greatly between tissues.

Answer 867

Interstitial fluid and prenodal lymph have probably the same composition of plasma proteins; lymph duct can be cannulated for fluid collection.

Answer 868

Proteins levels in lymph represent between 23% (skin) and 70% (lung) of the plasma concentration. Interstital COP is therefore far from negligible, and substantially reduces the absorptive force into plasma..

Answer 869

Starling pressures in human subcutaneous tissue (mmHg in normal subjects and in people affected by CHF. See table 9.1

Answer 870

This is because there is a simultaneous input of water from the capillaries.

Answer 871

In the steady state, the interstitial protein concentration (C1) and therefore interstitial COP, depends on the rate of protein arrival relative to the rate of water arrival. See Fig 9.7a If water filtration were to case altogether, the interstitial concentration would gradually rise to plasma level due to diffusion.

Answer 872

When capillary pressure and filtration rate are increased, interstitial protein concentration falls because the water flow increases more than the protein flux. It is true that protein flux increase too, due to increased convective transport, but this increase is not as great as the rise in water flow owing to the reflection of protein by the small pore system

Answer 873

There is a limit to the decline in interstitial protein concentration and COP and this limit is set by the average reflection coefficient of the capillary wall to plasma proteins.

Answer 874

At high filtration rates protein transport by diffusion or vesicles is relatively negligible.

Answer 875

Interstital COP is not only a determinant of filtration rate, but also a function of filtration rate.

Answer 876

Interstitial space is not simply a pool of liquid, but has a complex fibrous structure. See Fig 9.8.

Answer 877

The space is intersected by periodic collagen fibrils of diameter 20-50 nm (collagen I and III) and microfibrils of diameter ca 10 nm (collagen type VI), and the inter-fibrillar spaces are themselves subdivided by a class of fibrous molecule called glycosaminoglycan (GAG).

Answer 878

These are long-chain polymers of amino sugars, and the chief types are hyaluronate, keratin sulphate, dermatan sulphate, heparin sulphate and chondroitin sulphate.

Answer 879

The sulfated GAGs are up to 40 nm long, whilst hyaluronate is several micrometers long.

Answer 880

The sulphate and carboxyl groups of the GAGs represent fixed negative charges and this has an important effect on interstitial pressure.

Answer 881

The resistance to flow through such tiny spaces is very high and as a result the interstitium behaves mush like a gel Cells are not so much "bathed" in instersitiual fluid (a misleading metaphor) as "set" in a gel

Answer 882

1) Preventing a flow of interstitial water down the body under the drag of gravity 2) Impeding bacterial spread 3) Influencing the pressure-volume curve of the interstitial space.

Answer 883

The energy level of the interstitial liquid depends not just on mechanical pressure but also on the influence on the interstitial GAGs, and both these effects are rolled into one in the Starling term "interstitial pressure" (Pi)

Answer 884

Equilibrium pressure is slightly subatmospheric in many tissue (around -5 mmHg). The maintenance of the sub atmospheric pressure in the face of a continual input of fresh capillary ultra filtrate is probably due to suction of fluid from the tissues by lymphatic vessels

Answer 885

Pressure is above atmospheric in encapsulated organs like the kidney (1 to 10 mmHg) in certain muslces, myocardium, bone marrow and flexed joints.

Answer 886

Contrast, for ex, the dependent foot where capillary pressure is far higher than plasma COP and the lung where pressure is much lower than plasma COP.

Answer 887

Virtually all tissues form lymph, including the lung, providing that there is normally a net filtration of fluid out of the microcirculation.

Answer 888

The fraction of plasma filtered per transit (the filtration fraction) is actually very small in most tissues; around 0,2-0,3%, but since 4000 litres or so of plasma pass through an adult subject's microcirculation each day, a large volume of fresh interstitial fluid is generated over the course of a day, probably about 8-12 litres in an human.

Answer 889

Lymphatic drainage ensures that the interstitial volume remains normal despite this large input. In certain tissues, such as the renal glomerulus, salivary gland and dependent foot the filtration fraction is around a hundred times higher, being 20% in glomerular capillaries.

Answer 890

Plasma colloid osmotic pressure does not change significantly because the filtration fraction is small, but capillary pressure falls progressively with distance.

Answer 891

The flow of thoracic duct lymph is quite low, at most 4 litres per day in an adult, and this leads physiologists to believe that some of the capillary filtrate is reabsorbed directly into the blood stream. When and where this absorption takes place is, however, not well understood.

Answer 892

Textbooks have traditionally depicted fluid filtration out of the arterial half of the capillary and reabsorption into the venous half, because Pc falls below Pi p in the venous segment. (The Landis model of exchange). But as shown in Fig 9.10a, this view is untenable for well-perfused capillaries when modern measurements of interstitial COP and interstitial pressure are taken into account.

Answer 893

Vasoconstriction can reduce the capillary pressure sufficiently for the Landis filtration-absorption model to develop transiently (Fig 9.10b), but even then the downstream absorption cannot be maintained because the absorption process raises the interstitial protein concentration and Pip (symbol för Pi + nersänkt p) and lowers Po, and these changes gradually abolish the net absorptive force (Fig 9.10c); the absorption fades away with time.

Answer 894

If filtration ceases, protein accumulates outside the wall and progressively reduces the COP difference upon which absorption depends, until finally absorption ceases. It is probably therefore that reabsorption occurs transiently in most tissues during periods of arteriolar vasoconstriction, and occurs chiefly at the venous end of the microcirculation.

Answer 895

Fortunately, from the point of view of fluid balance, the absorption rate across the venular walls is enhances by their greater hydraulical conductance.

Answer 896

Thus fluid exchange downstream may oscilate between periods of filtration and transient reabsorption.

Answer 897

The functional mean capillary pressure is calculated to be very close to venous pressure; so there is only small net filtration force (perhaps as little as 0,5 mmHg) and a low lymph flow.

Answer 898

The lung is an important ex of the steady star reached when capillary pressure (approx 10 mmHg) is less than plasma COP (25 mmHg). Although these values might suggest, superficially, that lung capillaries are absorbing fluid , the lung in fact produces lymph, showing that the capillaries have a net filtration pressure.

Answer 899

The cause of the net filtration pressure is that lung interstitial fluid has a high protein concentration (approximately 70% plasma level) with a COP of 16-20 mmHg, which greatly reduces the net absorptive force Fig 9.11

Answer 900

renal tubular capillaries, in intestinal mucosal capillaries, and probably in lymph node capillaries. This is possible because the interstitial space in these tissues has a second input of fluid in the form of renal tubule absorbate, gut lumen absorbate or lymph respectively. This fluid flushes the interstitial space and prevents the accumulation of interstitial plasma protein.

Answer 901

In the cat intestine, 80% of the intestinal absorb ate is absorbed into the microcirculation while 20% acts as flushing solution and drains into the lymphatic vessels; in the kidney the corresponding figures are 99% and 1%.

Answer 902

If the plasma volume is reduced by a hemorrhage, some of the interstitial fluid is absorbed to top up the plasma; conversely, if plasma volume is increased by renal fluid retention or over-infusion, the excess fluid can "spill over" into the interstitium, raising the interstitial volume and therefore pressure.

Answer 903

In subcutaneous interstitium.

Answer 904

In normally hydrated interstitium, the fluid pressure is slightly subatmospheric, and small changes in volume affect the pressure markedly

Answer 905

compliance

Answer 906

This is because any removal of water raises the GAG concentration, which makes the gel swelling pressure more negative and opposes further volume change.

Answer 907

Beyond this point, the accumulation of fluid is no longer opposed by changes in GAG swelling pressure:the only opposition comes from the stretching of the collagen and elastin network. Since the subcutaneous network is rather loose, and the overlying skin highly distensible, this opposing force is small: moreover, it decays with time (a process called stress relaxation or delayed compliance). Interstitial compliance therefore increases rather abruptly just above atmospheric pressure, to around 20 times normal. Large volumes of fluid then accumulate with little opposing rise in pressure, and this creates pools of freely mobile liquid ---a condition called edema.

Answer 908

In an edematous leg, about 98% of the excess fluid is found in the subcutaneous plane, and its pressure is only just above atmospheric.

Answer 909

Owing to the low hydraulic conductivity of the interstitial matrix. The hydraulic conductivity of the interstitial matrix depends on the ratio of the fractional water content to the surface area of the fixed proteoglycan and collagen fibres, which are the source of hydraulic resistance.

Answer 910

In oedematous tissue, finger pressure leaves behind a distinct pit, indicating that free, abnormally mobile fluid had accumulated in the interstitium.

Answer 911

Chronic lymphoedema, in which the tissue reacts to high plasma protein levels in the edema fluid by synthesizing collagen and fat. This produces a fibrotic kind of edema that down not pit easily.

Answer 912

Protein transport through the interstititum: Small solute like glucose move easily through the interstitial proteglycan meshwork, larger solutes like albumin, however, experience a modest restriction and steric exclusion when diffusing through the interstitial matrix.

Answer 913

1)Preservation of fluid balance. Lymph vessels return capillary ultra filtrate and plasma proteins to the bloodstream at emptying points into the neck veins, and some fluid also return to the blood in the lymph nodes. This completes the extravascular circulation of fluid and protein and secures the homeostasis of tissue volume. See Fig 9.14

Answer 914

Preservation of fluid balance. Sine the plasma volume circulates in this fashion in less than 24 h, any impairment of lymphatic function leads to a severe protein-rich edema.

Answer 915

The brain and eye, which lack a normal lymphatic system, have unique fluid-draining system.

Answer 916

2. Nutritional function. Intestinal lymph vessels (lacteals) absorb digested fat in the form of tiny globules or chylomicra, and transport them to the plasma.

Answer 917

Defence function: Fluid draining out the interstitial compartment carries with it foreign materials such as soluble antigens, bacteria, carbon particles etc. These are carried in afferent lymph to the lymph nodes scattered along the drainage route (see Figure 9.15), providing an effective and economical method for the immunosurveillance of virtually the whole body.

Answer 918

Particulate matter is filtered out and phagocytosed in the nodes. Antigens stimulate a defensive lymphocyte response and the activated lymphocytes and plasma cells enter the efferent lymph (which has a much higher cell count than afferent lymph) for transport to the circulation.

Answer 919

The lymphatic system begins as a set of lymphatic capillaries (terminal lymphatics, initial lymphatics), which are either blind terminal sacs, as in intestinal villi, or else an anastomosing network of tubes of diameter 10-50 um. See Fig 9.15

Answer 920

Lymphatic capillaries: The very thin wall consists of a single layer of endothelial cells resting on an incomplete basement membrane. Some of the cell junctions are 14 nm wide or more, so lymphatic capillaries are highly permeable to plasma proteins and even to particulate matter like carbon.

Answer 921

The junctions run very obliquely and may function like flap valves, allowing fluid to enter readily but closing to prevent egress when lymph pressure rises above interstitial pressure (see Fig 9.16). The outer surface of the wall is tethered to the surrounding tissues by radiating fibrils, the anchoring filaments, which may help dilate the vessels in edematous tissue.

Answer 922

Lymphatic capillaries unite to form collecting vessels, which feed into the afferent lymph trunk alongside major vascular bundles like the popliteal vessels.

Answer 923

Semilunar valves direct the lymph centrally.

Answer 924

From the collecting vessels onwards the lymphatics possess a coat of smooth muscle and connective tissue, the muscle element being abundant in man and ruminants, but scanty in the dog and rabbit.

Answer 925

Several afferent vessels drain into the hilum of each lymph node. The node is a complex cellular body containing maturing lymphocytes in germinal centers, plus many phagocytic cells.

Answer 926

the afferent lymph flows thoughts sinuses, which are endothelial tubes with frequent gaps through which mature lymphocytes can enter the lymph.

Answer 927

If the afferent lymph presents a foreign antigen to the node, the generation and release of lymphocytes into postnodeal lymph increases dramatically and some lymphocytes develop into "plasma cells", which secrete gamma-globulin antibodies. The node is supplied with nutrients by a network of continuous capillaries, and these drain into special high-endothelial venules. Lymphocytes in the bloodstream re-enter the node by penetrating the intercellular junctions of the high-endothelial venues, thus completing their own unique circulation.

Answer 928

Lymphocyte-rich efferent lymph from the lower limbs and viscera flows into a large lymphatic trunk on the posterior abdominal wall. This possesses a sacular dilation, the cistern chyli, which acts as a temporary receptacle for chyle, the fatty lymph arriving from lacteals during absorption of a fatty meal.

Answer 929

The ultimate lymphatic trunk, the thoracic duct, receives around 3/4 of the body's efferent lymph and empties into the left subclavian vein at its junction with the jugular vein. The small cervical and right lymphatic trunks have much smaller flows.

Answer 930

The composition of prenodal lymph indicates that lymph is simply interstitial fluid drawn from the neighborhood of the lymphatic capillary; the concentration of electrolyte, non-metabolized solutes and plasma protein in prenodal lymph matches that in samples of interstitial fluid.

Answer 931

The likely answer is that first the lymphatic capillary empties proximally, either because it is compressed by the surrounding tissue during movement or because of contractions of the lymphatic wall (see Fig 9.17). Then, as the vessel re-expands elastically (probably helped by the anchoring filaments) the pressure inside falls transiently elow interstitial fluid pressure, setting up a pressure gradient for filling (like a pasteur pipett; first squeezing the rubber bulb empty and then allowing its recoil to suck in fluid). The presence of lymphatic valve upstream ensures that back flow does not interfere with this process.

Answer 932

Once formed, lymph is moved along by both intrinsic and extrinsic mechanisms

Answer 933

Occur in lymph vessels with abundant smooth muscle, including those in the human leg, and the contraction rate is typically 10-15 per min. Functions very much like the heart: pump function, pacemaker, valves etc. Both the frequency and stroke volume of the lymphangion increase with lymph volume.

Answer 934

The chief extrinsic propulsion process is intermittent compression during movement. The flow of lymph from the leg of an anesthetized dog is greatly increased by passive or active flexion, and the flow of mesenteric lymph is enhanced by intestinal peristalsis. Extrinsic propulsion is obviously important for non contractile vessels.

Answer 935

The lymph valves permit lymph pressure to rise stepwise in successive segments so that the lymph finally drains into venous blood at several mmHg above atmospheric pressure.

Answer 936

Lymph nodes like the popliteal and iliac nodes are known to modify the volume and protein conc of lymph; post nodal lymph in the dog and sheep has up to twice the protein conc of pre nodal lymph, due mainly to absorption of water by the node's continues capillaries.

Answer 937

The liver (contributes 30-50% of thoracic duct flow). Hepatic lymph is particularly rich in plasma protein.

Answer 938

Intestinal lymph flow is abundant after a meal and makes the second greatest contribution to thoracic duct flow. Renal and lung lymph flows are substantial too. The limbs contribute a variable quantity of lymph depending on the exercise level.

Answer 939

The concentration of plasma protein in lymph varies from region to region and depends on the permeability and reflection coefficient of the tissue's exchange vessels, the molecular size and charge of the individual protein and the capillary filtration rate.

Answer 940

The rise in capillary pressure below heart level, illustrated in Fig9.4, increases the filtration rate in dependent tissues; the foot, for example, swells at an initial rate of around 30 ml/h. This is often noticed by people compelled to sit still for hours, and many find it necessary to unlace their shoes to ease the expanded foot.

Answer 941

capillary pressure declines above heart leve and causes a transient absorption of tissue fluid; which probably explains why earlobe thickness fall 2-3 mm during the daytime.

Answer 942

The overall effect of orthostasis, however, is increased filtration. Plasma volume falls by 6-12 % during a 40 min period of standing, with a corresponding rise in haematocrit and protein concentration. Plasma COP in students is found to increase fro 25 mmHg to 29 mmhg after an 8 h day involving sitting through lectures, reading in the library etc.

Answer 943

1. Increase in Ra/Rv. Arteriolar contraction in the dependent tissue increases the pressure to about 2/3 of the rise in arterial and venous pressures. This is a local response, not a baroreceptor reflex, and it involves the myogenic response and/or a local sympathetic axon reflex.

Answer 944

2. The skeletal muscle pump: Dynamic exercise reduces venous pressure, and this reduces capillary pressure corresponding. The muscle pump also enhances lymph transport.

Answer 945

3. Reduces blood flow: The depends vasoconstriction refereed to above reduces not only capillary pressure bot also blood flow. The low plasma flow, coupled with the increased filtration pressure, raises the filtration fraction enormously. This helps to offset the increased blood pressure there. The blood flow also causes temperature to fall, as is commonly experienced in dependent feet. There is no evidence that interstitial pressure changes significantly.

Answer 946

4. Reduces capillary filtration capacity. It is possible that the constriction of some terminal arterioles may stop flow completely through capillary modules for short periods, lowering the local filtration capacity.

Answer 947

During exercise, local vasodilation not only increases muscle blood flow but also increases capillary pressure by reducing Ra/Rv. At the same time, the number of perfused capillaries is increased. As a result the filtration rate rises in exercising muslce and the muscle can swell by 20" over the course of 15 min.

Answer 948

An additional factor promoting swelling is the release of small solute like lactate and K+ by the active muscle fibres, which increases the interstitial osmolarity.

Answer 949

A compensatory absorption of interstitial fluid into plasma from non-exercising tissues, which minimizes the fall in blood volume.

Answer 950

The subcutaneous plane (peripheral edema) and the lungs (pulmonary edema).

Answer 951

Sc edema is not detected clinically until the interstitial volume has increased by about 100% (well along the compliance curve), which corresponds to a 10% increase in limb size.

Answer 952

Most commonly caused by LV failure, which elevates the left side filling pressure and therefore pulmonary venous pressure (whereas RV failure causes peripheral, sc edema).

Answer 953

Pulmonary oedema has serious consequences, partly because the stiff edematous lung is difficult to inflate, causing dyspnea (difficulty in breathing), and partly because the gas-to-blood distance increases, slowing down gas exchange and causing hypoxia. If the interstitial edema spills over into the alveolar spaces and floods them, pulmonary edema can be fatal.

Answer 954

Oedema develops when the capillary filtration rate exceeds the lymphatic drainage rate for a sufficient period, i.e. the pathogenesis involves either a high filtration rate or low lymph flow.

Answer 955

Since the factors governing filtration are given in the Starling expression, the terms of this equation provide a logical classification for edema. Equation 9.3

Answer 956

Elevation of capillary pressure is usually secondary to chronic elevation of venous pressure cause by ventricular failure or fluid overload (as in overtransfusion and acute glomerulonephritis), or deep venous thrombosis /which raises post capillary resistance and may later lead to venous valve incompetence).

Answer 957

Pressures of 20-40 mmHg develop in the venous limbs of skin capillaries during RV failure. The edema fluid in such cases has a reduced protein level; namely 1-10 g/litre, due to diluting effect of a high filtration rate.

Answer 958

Hypoproteinaemia raises lymph flow as well as net capillary filtration rate. See Fig 9.18. At the same time the lymph protein concentration falls and these changes provide some protection agains edema formation.

Answer 959

Clinically, it is found that overt edema only develops when the protein concentration in plasma falls below 30 g/litre.

Answer 960

1. Malnutrition or malabsorption due to intestinal disease, 2. By excessive loss of plasma protein either into the urine (nephrotic syndrome) or into the gut lumen (protein-losing enteropathy). The nephrotic syndrome is characterized by albuminuria due to leakage of albumin through the glomerular membrane, often exceeding 20 g/day. 3. or by hepatic failure, the liver being the site of synthesis of the plasma proteins albumin, fibrinogen, alpha-globulins and beta-globulins. The commonest cause of hepatic failure is a fibrotic condition called cirrhosis, which give rise to abdominal edema (ascites) by raising portal vein pressure as well as lowering plasma COP.

Answer 961

In inflammation, the properties of the capillary wall itself change;hydraulic conductance and protein permeability increase and the reflection coefficient decreases. This causes a severe high-protein edema.

Answer 962

Impairment of lymphatic drainage causes the accumulation of both fluid and protein since both enter the interstitial space in substantial amounts over a day. Fig 9.14

Answer 963

Because lymph is the sole route for returning escaped protein to the plasma, lymphoedema fluid is rich in protein.

Answer 964

The high interstitial COP exacerbates the edema by raising the net filtration force across the capillary wall.

Answer 965

Chronic exposure of the tissue to the highly proteinaceous edema fluid evokes a fibrotic-fatty overgrowth, so long-standing lymphoedema does not pit easily.

Answer 966

In western countries lymphatic insufficiency is usually due either to poor formation of limb lymph trunks (idiopathic lymhoedema) or to damage to lymph nodes during cancer therapy. See Fig 9.19. The commonest cause world-wide, however, is filariasis, a nematode worm infestation transmitted by mosquitos.

Answer 967

15 mmHg There is thus a margin of safety against edema of 15 mmHg or thereabouts, and this is due to three buffering factors; 1. changes in interstitial fluid pressure, 2. changes in interstitial COP and 3. changes in lymph flow. Fig 9.20

Answer 968

This mechanism fails above 1 to 2 mmHg in tissues where compliance increases sharply.

Answer 969

2. Changes in interstitial COP/pressure: An increase in filtration rate lowers the interstitial and lymph protein concentration. This lowers the interstitial COP and thereby increases the absorptive force. Table 9.1. Like mechanism 1, this buffer has a limited capacity, because the ratio of interstitial plasma protein conc can fall no lower than 1 - sigma (Fig 9.7). Interstitial dilution is most effective as a buffer mechanism in tissues where the interstitial protein conc is normally high: e.g the lung.

Answer 970

Interstitial dilution is most effective as a buffer mechanism in tissues where the interstitial protein conc is normally high: e.g the lung.

Answer 971

3. Increased lymph flow: when interstitial volume and pressure increase, the lymph flow from the tissue increases too:

Answer 972

15 mmHg. In most tissues, changes in interstitial COP seems to be the major buffer.

Answer 973

The lung in particular is well protected against edema by its high interstitial COP:

Answer 974

vasodilation caused by locally-released substances. These chemical mediators of inflammation include histamine, bradykinin, prostaglandin, subsance P, platelet-activiting facts, superoxide radicals and others.Most of these substances, plus the potent leukotrienes and cytokines also initiate a series of changes in the walls of pericytic venules.

Answer 975

Cytokines are mediators of the inflammatory response produces by monocytes, endothelial cells and fibroblasts. They include TNF and the interleukin series.

Answer 976

the endothelial surface becomes attractive to polymorphonuclear leukocytes. These adhere to the wall (margination) and then push through the intercellular junctions to invade the inflamed tissue. They are followed more slowly by migrating lymphocytes.

Answer 977

Quite independently of leukocyte migration some endothelial junctions open up into gaps as much as 0,5 um wide. See Fig 9.21. Gap formation is thought to be due to the contraction of the actin and myosin filaments that exist within endothelial cells, mediated probably by a rise in intracellular Ca2+. Gap formation in response to histamine can be reduced by the H1-receptor antagonist mepyramine and by the beta-adrenergic agonists isoprenaline and terbutaline.

Answer 978

The inflammatory swelling which ensues is caused partly by the gap formation and partly by changes in net filtration pressure.

Answer 979

Arteriolar vasodilation and a consequent fall in Ra/Rv

Answer 980

The hydraulic conductance of the wall increases many times; as can be seen from the increased slope in Figure 9.21.

Answer 981

The gaps also raise the permeability to plasma protein: This speeds the movement of immunoglobulins into the tissue but at the same time raises the interstitial concentration of plasma proteins, reducing the gradient of COP that opposes filtration. The gaps also lower the protein reflection coefficient to around 0,4, which further reduces the effective COP across the wall. See Fig 9.21b

Answer 982

Eventually the combination of a high filtration fraction and adhering leukocytes can lead to plugging of the capillary lumen by a packed column of red cells, a condition called vascular stasis.

Answer 983

Inflammation is a high-permeability disorder and the edema fluid has high protein concentration; it is sometimes called an "exudate" by way of contrast with the low protein edema or "transudate" of venous hypertension and hypoproteinaemia.

Answer 984

Large volumes of exudate can form in the peritoneal, pleural, pericardial and synovial cavities during local inflammatory conditions (e.g peritonitis, pleurisy, pericarditis, rheumatoid arthritis), and the exudate contains relatively high concentrations of fibrinogen owing to the loss of molecular selectivity at the capillary gaps. Fibrin adhesions can the develop and complicate the disease (e.g intestinal adhesion after peritonitis).

Answer 985

A recently-developed concept whereby, after a period of poor perfusion due to vascular obstruction, the restoration of blood flow delivers oxygen which is partly converted into toxic superoxide radicals by the tissue. These radicals damage the endothelium, leading to inflammation and impairment of tissue recovery, e.g. after myocardial infarction.

Answer 986

The interstitial compartment represents a reservoir of fluid, some of which can be transferred to the plasma after a hemorrhage or any other form of hypovolaemia (low blood volume), such as dehydration.

Answer 987

In hypovolemia, a sympathetically mediated arteriolar construction raises Ra/Rv. This, coupled with a fall in arterial and venous pressures, reduced the mean capillary pressure and produces a net absorption force across the capillary wall. A transient absorption of interstitial fluid ensues (see Fig 9.10), partially restoring the plasma volume but reducing the haematocrit and plasma protein concentration. This "internal transfusion" of fluid explains why most hemorrhage patients have a low haematocrit by the time they reach hospital.

Answer 988

a reduction in plasma COP due to haemodilution, a rise in interstitial COP and a fall in interstitial pressure. Nevertheless, as much as half a litre is absorbed from the interstitial compartment during the first hour after a severe hemorrhage; much of it comes from skeletal muscle, since this is 40% of the body weight.

Answer 989

Post-haemorrhagic glycolysis in the liver, induced by sympathetic-adrenal stimulation and glucagon. The output of glucose by the liver rises sharply and raises the osmolarity of plasma and interstitial fluid by as much as 20 mOsm. The rise in interstitial osmolarity draws fluid osmotically from the huge intracellular compartment into the interstitial compartment and this replenishment of the interstitial compartment allows capillary absorption to continue for 30-60 min, much longer than would otherwise be possible.

Answer 990

It is estimated that, overall, about half the internal transfusion comes ultimately from the intracellular compartment.

Answer 991

The tunica media of a blood vessel contains smooth muscle cells arranged in a helical pattern, and their degree of contraction controls the vessel radius and blood flow.

Answer 992

Spindel-shaped, about 20-60 um long and 4 um wide at the nuclear region. It contains thick filament composed of myosin, surrounded by numerous thin filaments composed of actin.

Answer 993

The actin:myosin ratio is about 8 times larger than in striated muscle. The actin filaments insert not into Z lines but into "dense bands" on the inter surface of the cell, and into "dense bodies" in the cytoplasm. These structures are composed of alpha-actinin, the same substances that form Z-imes in striated muscle.

Answer 994

No, because the contractile units are not aligned in register.

Answer 995

A third kind of filament, the intermediate filament, is also abundant in VSM. It is composed of the proteins filamin, actin, alpha-actinin and desmin. Not clear if involved in the contractile process.

Answer 996

The VSM cell possesses a system of smooth ER which forms about 2% of the cell volume and contains a releasable store of calcium ions. The membrane of adjacent cells are linked by electrically conductive "gap junctions", which allow depolarization to spread from cell to cell, so the cells form a functional syncytium. The spread is decremental, however, and extends only a millimeter or so along the axis of the vessel.

Answer 997

As in cardiac muscle, contraction is initiated by a rise in free Ca2+ ions in the cytoplasm, as proved by experiments with calcium-sensitive intracellular indicators.

Answer 998

Partly from the SR store and partly from the extracellular fluid via calcium channels in the cell membran.

Answer 999

2. The rise in free calcium causes the myosin filaments to form cross bridges with the actin filaments, and thereby "row" themselves into the spaces between the actin filaments, producing shortening and tension.

Answer 1000

1) Myosin light-chain phosphorylation: VSM myosin can only interact with actin after its light chains have been phosphorylate by ATP (the light chains are part of the cross bridge head. see Fig 3.3. A rise in cytoplasmic calcium causes the formation of the calcium calmodulin complex, which activates myosin light-chain kinase, leading to myosin phosphorylaton and cross bridging.

Answer 1001

The latch state. Striated muscle relies on the continuous, rapid maing and breaking of cross bridges to maintain tension (cross bridge cycling), and this is an energy-expensive process. VSM, however, can maintain an active tension for just 1/300th of the energy expenditure of striated muscle. This is achieved by the formation of long-lasting cross bridges called "latch bridges" which cycle only very slowly. It is thought that the latch bridges may be cross bridges that become dephosphorylated.

Answer 1002

In order to understand excitation contraction coupling in VSM, we must take account of a minimum of 3 different ion-conductin channels in the cell membrane, although many more are known.

Answer 1003

which results chiefly from the membrane being more permeable to potassium ions than to other ions. A Na+-K+ exchange pump in the cell membrane maintains a high intracellular K+ concentration, and an outward flux of K ions through the K+ channels down the potassium electrochemical gradient sets up a resting potential, rather as in myocytes.

Answer 1004

These channels are permeable to divalent cations like calcium and barium, and they open when the membrane depolarizes beyond a certain point. See Fig 10.4 They allow calcium to enter the cell, initiating by depolarizaiotn, this is termed electrochemical coupling.

Answer 1005

At least 2 types of calcium VGC exist in may VSM cells. Some have a low conductance, open at low threshold (around -50 mV) and the quickly self-inactives. Others have a larger conductance, open at a more positive threshold (-20 mV) and inactive more slowly. The channels with thresholds close ego the resting potential may be important in regulating basal tone.

Answer 1006

``` This class of calcium-conducting channel is insensitive to membrane potential but is activated when a chemical transmitter such as noradrenaline binds to its specific receptors on the cell membrane. This provides a second, depolarization-independent way by which noradrenaline can induce contraction, called pharmacomechanical coupling. Substances like vasopression, angiotension, and histamine are also able to cause contrition by activating ROCs. ```

Answer 1007

The aorta and the pulmonary arteries in some species, and the fine cerebral vessels.

Answer 1008

The sympathetic fibres run along the advential-medial border, and the inter part of the media is not directly innervated, except in veins. The terminal fibres bear a string of swellings called junctional variocosities. Each varicosity contains both small and large dense-cored vesicles, which contain a variable mixture of noradrenaline and ATP. On arrival of the nerve action potential there is a rise in intramural calcium ion concentration, which causes some vesicles to discharge their contents into the extracellular space. The neurotransmitter then quickly diffuses across the VSM cell membrane and binds to receptors there.

Answer 1009

hen the perivascular sympathetic fibres are excited by a brief small stimulus, they elicit an electrical response with 2 components: There is an initial rapid brief depolarization of the VSM cell, which is called an excitatory junction potential (EJP); this is not an action potential. The EJP is followed by a smaller, slower depolarization of longer duration (several seconds). The slow depolarization can be blocked by alpha-adrenorecptor antagonists like prazosin. Fig 10.2, so it is called a neurogenic alpha depolarization or NAD.

Answer 1010

ATP release.

Answer 1011

pharmacomechanical coupling

Answer 1012

If the stimulus strength is increased, the EJP becomes larger, reaches the threshold of the voltage-gated calcium channels and triggers an action potential; this elicits a short-latency brief contraction, i.e twitch.(see Fig 10.2b). The NAD becomes larger too and triggers another action potential; this produces a second twitch superimposed on the underlying slow contraction. The twitches are examples of electromechanical coupling, while the underlying slow contraction reflects pharmacomechanical coupling.. The action potential itself is a simple spike depolarization of rather variable amplitude, lasting 10-100 ms. The depolarization is due mainly to an influx of Ca2 ions into the cells as the voltage-gated calcium channels open. The twitch is due partly to Ca2+ ions arriving by this route and partly to Ca2+ ions released from the internal stores.

Answer 1013

It must be stressed that the response to sympathetic stimulation varies greatly from vessel to vessel, and not all vessels respond as above, though the pattern is common one. In some vessels, such as the pulmonary artery, NADs can be elicited without a preceding EJP (see Fig 10.3c), while in others under appropriate conditions, EJP are elicited without NADs.

Answer 1014

The induction of contraction by a chemical agent (whether released from a local nerve or circulating) without the necessity of a change in membrane potential or the firing of an action potential.

Answer 1015

In certain vessels, such as the pulmonary artery, the superfusion of noradrenaline at a low concentration causes a sustained contraction without any detectable membrane depolarization.

Answer 1016

Even actionpotential-generating vessels such as the portal vein (see Fig 10.3a) can be induced to contract without action potentials if their VGCs are blocked by verapamil

Answer 1017

1. one mechanism is the opening of the receptor-operator channels, which allows extracellular calcium ions to flow into the cell and initiated contraction. 2. A chain of biochemical reactions, in which a membrane protein called a "G-protein" activates the enzyme phospholipase C. The latter catalyses the production of an intracellular "second messenger", inositol triphosphate (IP3), which acts on the sarcoplasmic reticulum to induce the release of stored Ca2?.

Answer 1018

Automaticity: in most arteries and veins, the VSM cell have a stable resting potential but in some vessels (protein vein, terminal pail arteries and arterioles) the resting potential is unstable and depolarization occurs spontanesously, triggering action potentials and spontaneous contractions. See Fig 10.3a). The process bear some resemblance to that in SA node cells, though it is less regular. The excitation then spreads from cell to cell via the gap junctions.

Answer 1019

If most of the VSM cells contract synchronously the vessel undergoes rhythmic variations in calibre producing the vasomotion often seen in small arterioles.

Answer 1020

The control of blood vessels can be conceptualized fairly simply as a hierarchy of three control system, each able to override the lower one.

Answer 1021

The tunica media of blood vessels contains smooth muscle cells arranged in a predominantly circumferential pattern and the active tension of these cells controls the radius of the vessel, as explained previously. It is worth reiterating here that vasodilatation is a passive, not active process, being powered by the blood pressure, and recoil of elastic elements in the wall as vascular smooth muscle relaxes.

Answer 1022

1) Local arteriolar resistance regulates blood flow to the tissue downstream of the arteriole. The range of flows that can be produced is enormous in some organs. In general, the flow is varied to match the metabolic activity of the tissue. 2) The total arteriolar resistance, acting in concert with the cardiac output, regulates the systemic arterial pressure. 3) Capillary recruitment and capillary filtration pressure are both regulated by local arterial tone, as shown in Fig 8.15 and 9.4, respectively. Thus, arteriolar radius exerts both local effects (control of nutritive supply and organ fluid balance) and central effects (homeostasis of blood pressure and plasma volume).

Answer 1023

The veins and venues normally contain around 60% of the blood volume, and a decrease in the average radius of the peripheral veins and venues can displace a considerable volume of blood into the central veins. Venous smooth muscle can thus influences the cardiac filling pressure, and hence stroke volume.

Answer 1024

The total active tension of the vascular smooth muscle (VSM) in a segment of wall is called the vessel tone. Owing to the automaticity of their VSM cells, the arterioles and some larger vessels retain a degree of tone (i.e remain partially contracted) even when their sympathetic innervation is interrupted, and this is called the basal tone

Answer 1025

A high basal tone is vital if a vessel is to be capable of substantial dilatation because dilatation is simply a reduction in tone.

Answer 1026

The grater the basal tone the greater the potential for vasodilatation.

Answer 1027

Tissues which are capable of producing large increases in blood flow, such as skeletal muscle and the salary gland (Fig 11.1) have a high basal tone. By contrast, basal tone is slight in most veins.

Answer 1028

The tone of a vessel in vivo is influenced by numerous factors which fall into 2 broad categories; local or intrinsic control mechanisms and extrinsic control mechanisms (see Fig 11.2)

Answer 1029

Intrinsic control mechanisms are located entirely within the organ and include physical factors (temperature, pressure), the myogenic response, tissue metabolites and autocoids. Extrinsic control mechanisms are the autonomic nerves and circulating endocrine secretions.

Answer 1030

This is particularly important in the skin. High ambient temperatures cause the cutaneous arterioles and veins to dilate producing the familiar reddening of a limb immersed in hot water. Conversely, skin temp down to 10-15 grader cause vasoconstriction which conserves heat and safeguards core temperature.

Answer 1031

The vasoconstrictor response to cold is attributed partly to slowing of the Na-K pump in the VSM membrane, which leads to depolarization, and partly to an increase in the affinity of the cutaneous VSM adrenoreceptors for noradrenaline as temperature falls.

Answer 1032

Cooling below approximately 12 grader, by contrast, leads to paradoxical cold vasodilation (see chapter 12) which is caused by the impairment of neurotransmitter release and by the release of vasodilator substances like prostaglandins from the underperfused tissue.

Answer 1033

A high external pressure compresses the vessels and impairs blood flow, as in skeletal muscle during its contraction phase. See Figure 11.6. Similarly, flow through the skin is impaired by compression during sitting, kneeling, lying etc, and should a patient be bedridden by age or paralysis, the prolonged impairment of skin nutrition can result in large ulcerating bed sores.

Answer 1034

myogenic response.

Answer 1035

The myogenic response safeguards blood flow and capillary filtration pressure in the face of changes in blood pressure, and also contributes to the basal tone of the vasculature.

Answer 1036

The immediate cause of the myogenic response in spike-generating vessels, like the arterioles and portal-mesentreric vein, is that stretch increases the frequency of the spontaneous action potentials resulting in increased active tension. (see Fig 7.12. Such a region might initiate spike activity.

Answer 1037

vasoconstrictor

Answer 1038

Many of the chemical by-products of metabolism cause vascular relaxation, so any increase in tissue metabolic rate causes arteriolar dilatation and automatically increases the local tissue perfusion. This process is called metabolic vasodilation.

Answer 1039

The increase in blood flow is almost linearly proportion to metabolic rate in tissues, such as exercising muscle, myocardium and brain, provided that the arterial pressure is constant.

Answer 1040

- Hypoxia - Acidosis due to the release of carbon dioxide and lactic acid - Breakdown products of ATP, namely adenosine diphosphate (ADP), adenosine monophospate (AMP), adneoinse and inorganic phosphate. - Potasssium ions released by contracting muscle and (in the brain) by active neurons - A rise in interstitial osmolarity due to the release of lactate, K+ and other small solutes.

Answer 1041

The relative importance of each factor varies from organ to organ; cerebral vessels for ex are particularly sensitive to H+ and K+ ions, while coronary vessels are influenced chiefly by hypoxia and/or adenosine.

Answer 1042

The relative importance of each factor varies from organ to organ; cerebral vessels for ex are particularly sensitive to H+ and K+ ions, while coronary vessels are influenced chiefly by hypoxia and/or adenosine.

Answer 1043

A moderate increase in extracellular K+ conc cause the membrane potassium conductance to increase; this brings the potential equilibrium potential, so the membrane hyperpolarizes and relaxation follows.

Answer 1044

Higher extracellular potassium conc reduce the potassium gradient across the VSM membrane to such an extent that the membrane depolarizes and vasoconstriction ensues.

Answer 1045

Vasoactive chemicals that are produced locally, released locally and act locally (unlike endocrine secretions). They are involved chiefly in special local responses such as inflammation and homeostasis.

Answer 1046

Histamine, bradykinein, 5-hydroxytryptamine and the prostaglandin-thromboxane-leukotriene group.

Answer 1047

It is found in granules within mastcells and basofiles. It is one of the chemical mediators of inflammation, being released in response to trauma and certain allergic reactions (urticaria, anaphylaxis).

Answer 1048

Dilates arterioles, constricts veins and increases venular permeability.

Answer 1049

Exocrine glands like the salivary gland and sweat glands secrete the enzyme kallikrein into their ducts when stimulated by cholinergic nerves. If kallikrein back-diffuses into the inerstitium (following duct obstruktion) bradykinin is produced by different steps.

Answer 1050

Bradykinin is a strong vasodilator agent, and also increases venular permeability.

Answer 1051

This derive of the amino acid tryptophan is found in platelets, the interstitial wall and the central nervous system.

Answer 1052

haemostasis.

Answer 1053

In the intestinal tract, 5HT occurs in argentaffin cells and may be involved in the regulation of local blood flow, and GI smooth muscle.

Answer 1054

hypertension and diarrhea.

Answer 1055

In the brain, 5HT occurs in neurons close to cerebral vessels; it markedly potentiates the effect of noradrenline and may be involved in the vasospasm associated with migraine and subarachnoid hemorrhage.

Answer 1056

5HT is also a central neurotransmitter, and the hallucinogenic drug lysergic acid diethylamice (LSD) is an antagonist of 5HT.

Answer 1057

These are vasoactive agents synthesized from a fatty acid precursor; arachidonic acid, via the enzyme cyclo-oxygenase.

Answer 1058

Macrophages, leukocytes, fibrobalsts and endothelium.

Answer 1059

The F-series (PGF) are mainly vasoconstrictor agents

Answer 1060

The E series (PGE) and prostacyclin (PGI2) are vasodilator substances (see Fig 11.4)

Answer 1061

The vasodilator prostaglandins contribute to inflammatory vasodilation and reactive hyperemia, and their synthesis is inhibited by aspirin and indomethacin.

Answer 1062

The related arachidonic-acid derivate, thromboxane A2, is a powerful vasoconstrictor substance found in platelets, it is involved in platelet aggregation and homeostasis.

Answer 1063

Eicosanois

Answer 1064

This group of vasoactive substances is produces from arachidonic acid by a different pathway, involving the enzyme lipoxygenase.They are synthesized by leucocytes and are important mediators of the inflammatory respons

Answer 1065

Vasoconstrriction, leukocyte margination and emigration, and formation of gaps in the walls of venues. Their gap-inducing action develops at 1000th the concentration at which histamine acts.

Answer 1066

The response of pulmonary resistance vessels to chemical factors is often different from the response of systemic vessels. Alveolar hypoxia, for ex, cause pulmonary vasoconstriction, not dilatation. This is physiologically important, for it reduces the perfusion of underventilated regions and thereby helps to maintain a normal ventilation-perfusion ratio.

Answer 1067

If hypoxia is generalized, as at high-atitude, pulmonary hypertension results from this response. The pulmonary vascular response to many other agents is reversed also; histamine and bradykinin, for ex, causes pulmonary vasoconstriction.

Answer 1068

Bradykinin, ADP, substance P, and, in certain tissues/species, histamine.

Answer 1069

EDRF is produced too in response to endothelial shear stress, and this accounts for the long-recongnize phenomenon of flow-induced vasodilation in arteries; when flow through a large artery is increased (due to a fall in downstream arteriolar resistance), the artery dilates, facilitating blood flow to the arterioles. It should be noted, however, that that the vasodilator effect of many substances is not EDRF-dependetn (e.g adenosine, AMP, isoprenaline, papaverine, nitrodilators), while for other substances EDRF involvement varies between tissues and species.

Answer 1070

The half-life of EDFR is extremely short (approximately 6 s) and it is now clear that EDFR is in fact nitric oxide (NO), which is cleaved-off the amino acid arginine by an endothelial enzyme. Blockage of this enzyme by the sable analogue L-methyl argentine causes a rise in arterial pressure in the intact animal, from which it is deduced that EDRF production occurs continuously and exerts a tonic vasodilator influence on the resistance vessels.

Answer 1071

Organic nitrates like glycerol trinitrate have long been used as vasodilator drugs in the treatment of angina, and it is now perceived that they act by mimicking EDRF and real sing nitric oxide into the tissue.

Answer 1072

Endothelium can produce not only dilator substances but also vasoconstrictor compound. One vasoconstrictor substance appears to be a prostanoid, i.e. a product of cyclo-oxygenase; it mediated the contractile response of larger arteries to hypoxia. Another agnet is a peptide called endothelia, which causes a strong vasocontricion lasting 2-3 h.

Answer 1073

Several major circulatory adjustments can be initiated by the above local mechanisms rather than by extrinsic neural control: the most important examples are auto regulation, metabolic hyperemia and reactive hyperemia.

Answer 1074

The relative constancy of tissue perfusion in the face of pressure changes.

Answer 1075

the resistance vessels respond directly to the changes in arterial pressure, a rise in pressure evokes vasoconstriction and a rise in vascular resistance while a fall in pressure evokes vasodilation and fall in resistance. This accounts for the near constancy of the flow.

Answer 1076

Cerebral blood flow, for example, is well maintained during spinal anesthesia, despite the concomitant systemic hypotension induced by this procedure.

Answer 1077

As well as stabilizing the tissue perfusion, autoregulation also stabilizes capillary filtration pressure.

Answer 1078

Capillary pressure depends on the pre- to post capillary resistance ratio, and the autoregulatory changes in pre capillary resistance protect the capillaries from changes in arterial pressure.

Answer 1079

Autoregulation of capillary pressure is particularly important in the kidney where it ensues a virtually constant glomerular filtration rate.

Answer 1080

Autoregulation operates only over a limited range of pressure, however, and cerebral blood flow, renal function etc fall off during severe hypotension.

Answer 1081

2 mechanisms mediate autoregultation in most organs, namely the myogenic response and vasodilator washout.

Answer 1082

Vasodilator washout refers to the effect of blood flow on locally produced vasodilator substances: If blood flow is increased transiently by a rise in arterial pressure, vasodilator products of tissue metabolism are washed out and their interstitial concentration declines, allowing vessel tone to increase.

Answer 1083

Venous back-pressure stretches the arterioles and this would be expected to elicit a myogenic constriction and an increase in vascular resistance, but venous congestion also reduces the flow, reducing the washout of vasodilators and producing vasodilation.

Answer 1084

In practice, venous congestion elicits vasoconstriction in the brain, intestine, colon, liver, and spleen, indicating a myogenic predominance, while in skin and skeletal muscle the effect is variable, indicating an approximate equipotence of the 2 mechanisms.

Answer 1085

It must be emphasized that while autoregulation is an intrinsic property of most vascular beds (except the lungs), this does not mean that blood flow and capillary pressure are necessarily constant in the intact animal.On the contrary, they are frequently altered by changes in sympathetic drive and changes in local metabolic rate, which reset auto regulation to operate at a new level.

Answer 1086

vascular resistance. The hyperemia is evidently caused by a fallin vascular resistance. The fall is induced by vasodilator substances that are released by the tissue, eg. adenosine, K+, H+. In addition, most of these agents inhibit the release of noradrenaline from sympathetic fires.

Answer 1087

Sustained vasodilation seen in active muslce and myocardium is caused hy the locally-produced vasodilator substances and not by vasomotor nerves. It should also be noted that while the increase in blood flow is a local or "automatic" process, it is not an example of auto regulation, for auto regulation is by definition is by definition a relative constancy of flow in the face of changes in arterial pressure.

Answer 1088

If blood flow to a tissue is stopped completely for a period by compressing the supplying artery, or is sowed to the point where it is inadequate for tissue nutrition (ischaemia), the blood flow immediately after releasing the compression is much higher than normal, and then decyas exponentially.

Answer 1089

The myogenic response probably contributes significantly to the hyperemia that follows brief arterial occlusion (

Answer 1090

Prostaglandins too play a part for the hyperemia is reduced (but not abolished) by indomethacin, an inhibitor of cyclo-oxygenase. The greater the duration of the ischeamic period, the greater is the accumulation of vasodilator substances and the greater the total cumulative blood flow afterwards.

Answer 1091

The functional importance of reactive hyperemia lies in resupplying oxygen and nutrients to the ischaemic tissue as rapidly as possible.

Answer 1092

Reperfusion after long periods of ischeamia (over 30 min) can initiate tissue damage even though reperfussion is of course essential for the tissue´s long-term survival. Hypoxanthine is formed during the anoxic period as a breakdown product of ATP. Upon reperfussion, oxygen becomes available and the xanthine oxidase catalyses the oxidation of the hypoxanthine, but this oxidation reaction also results in the conversion of ordinary molecular oxygen into superoxide radicals (O2-.) and hydroxyl radicals (OH.)

Answer 1093

Radicals are highly reactive particles owing to a lone electron in the outer shell, and the hydroxyl radical in particular readily attacks cell membrane lipids, proteins and glycosaminoglycans. This damages the tissue and the capillary wall, causing leukocytes to adhere to the wall and obstruct flow (no-reflow" phenomenon).

Answer 1094

Reperfusion injury can be attenuated by pretreatment with allopurino (an inhibitor of xanthine oxidase) or superoxide dismutases (a superoxide scavenger) or dimethyl sulphoxide (a hydroxyl radical scavenger).

Answer 1095

Reperfusion injury is thought to contribute to myocardial, intestinal, and brain damage after thrombotic episodes, and possibly to joint damage in rheumatoid arthritis.

Answer 1096

Nervous control; sympathetic vasoconstrictor nerves: Local mechanisms serve only local needs. To serve the more general needs of the whole organism, such as the homeostasis of arterial pressure and core temperature, the control nervous system superimpose a sentient control system over the circulation.

Answer 1097

The efferent limb of this extrinsic system comprises autonomic vasomotor nerves and endocrine secretions, and the afferent limb involves sensory inputs.

Answer 1098

The autonomic vasomotor nerves fall into three classes: sympathetic vasoconstrictor fibres, sympathetic vasodilator fibres, and parasympathetic vasodilator fibres: this terminology refers to the effect of stimulating (cf. inhibiting) the nerve. Of these, the sympathetic vasoconstrictor fibres are the most widespread and important.

Answer 1099

Students accustomed to associating the sympathetic system with alarm and dilatation should note that the vast majority of the sympathetic vasomotor fibres are in fact vasoconstrictor fibres.

Answer 1100

The pathway controlling the sympathetic noradrenergic vasoconstrictor fibres begins in the brainstem. From here, descending excitatory and inhibitory fibres called bulbospinal fibres pass down the spinal cord and and synapse with sympathetic preganglionic neurons in the intermediolateral columns of the grey matter (thoracicolumbar segment T1 to L3). The output of these spinal neurons depends on the interplay of excitatory and inhibitory inputs by the bulbospinal fibres, plus local spinal inputs.

Answer 1101

The sympathetic preganglionic axons travel via the ventral roots of the spinal nerves and white rami communicates into the sympathetic chains and may travel up or down the chain for several segments before synapsing with postganglionic neurons located in the sympathetic ganglia.

Answer 1102

Some fibres do not synapse until they reach more distant ganglia (coeliac and hypogastric ganglia) or the adrenal medulla. The preganglionic fibres are cholinergic and the rectports on the cell bodes of the postfagnglionic neurons are of the nicotinic variety, belong blocked by hexamethonium.

Answer 1103

Bild 11.8 s 214

Answer 1104

The postganglionic cells of the sympathetic chain send non-myelinated axons through the grey rami communicants for distribution in the mixed peripheral nerves; some fibres also course directly over the major vessels. The terminal fibres run along the outer border of the tunica media but, except in veins, they do not penetrate the inner part owing to the higher pressure there.

Answer 1105

Most small arteries and large arterioles are richly innervated whereas terminal arterioles are poorly inntervated and are probably controlled chiefly by local tissue metabolite. This pattern is repeated in the splanchnic venous system, although venous vessels are in general less densely enervated, and the venous system of skeletal muscle received almost no innervation.

Answer 1106

The classical, long-recognized transmitter released by postganglionic sympathetic fibres is noradrenaline (norepinephrine). This quickly diffuses across the junctional gap and binds to alpha-adrenorecptors on the VSM cell membrane.

Answer 1107

NA quickly diffuses across the junctional gap and binds to alpha-adrenorecptors on the VSM cell membrane. There are 2 kinds of receptors: alpha receptors are widely distributed over the VSM membrane, while alpha2 receptors occur on the nerve fibre as pre-junctional receptors and on certain blood vessels (e.g human skin arterioles) along with the alpha 1 receptors.

Answer 1108

Activation of the post junctional receptors elicits vasoconstriction by pharmacomechanical and electromechanical coupling as described in chapter 10. About 80% of the NA s then taken back into the nerve by an active membrane process which terminates its action and restocks the terminal. To a lesser extent transmitter action is also terminated by diffusion into the nearby capillaries and by post junctional degrading enzymes (catechol-O-methyltransferase and monoamine oxidase)

Answer 1109

Local modulation of NA release: The amount of neurotransmitter released at the junction depends not just on impulse frequency but also on the chemical environment of the nerve (neuromodulation). As mentioned earlier, agents like H+, K+ adnadenosine act on the nerve membrane to depress the release of transmitter, and this contributes to metabolic hyperemia. Most autocoids have a similar effect.

Answer 1110

Noradrenaline too binds to pre junctional alpha2 receptors (autoreceptors) and this inhibits further release of NA. By contrast, angiotension II facilitates transmitter release and thereby amplifies vasoconstriction (see later).

Cardiovascular physiology Flashcards

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