Regulation of Vascular Function 1 and 2 (Ramchandra) Flashcards Preview

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Flashcards in Regulation of Vascular Function 1 and 2 (Ramchandra) Deck (29):
1

What Law is relavent when it comes to stretching of the blood vessels?

Frank Starling Law (more blood goes in- more stretch- more blood comes out)

2

Post capillary vessels have ________________________- than pre-capillary vessels of
similar vascular generation

Post capillary vessels have smaller
proportion of vascular smooth muscle
in
their walls than pre-capillary vessels of
similar vascular generation

3

______________nerves supply all
vascular beds in the body.

 

 

Veins are more sparsely
innervated than _______________, but innervation increases as the vessels get larger.

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Sympathetic adrenergic nerves supply all
vascular beds in the body.

 

 

Veins are more sparsely
innervated than equivalent pre-capillary vessels, but innervation increases as the vessels get larger.

4

Blood vessel dimensions are determined by.....

Vascular smooth muscle activity

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5

Describe the dsitribution of cardiac output in different situations

After eating, you distribute your blood so your GI tract receives more blood

 

After drinking, you distribute your blood so that your kidneys receive more blood (to excrete water)

 

When exercising, you distribute more blood to skin and muscles. 

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6

Describe the movement of water between circulation and interstitial space with changes in the pre-capillary diameter. 

Hydrostatic pressure moves fluid out (red)

 

When the pressure in the tissue is higher than the venous system/post-capillaries, fluid is reabsorbed. (Blue)

 

If you increase the pre-capillary resistance (e.g. a clamp),  the pressure post-that clamp will fall,  which will favour reabsorption. (Blue line)

 

If you reduce the precapillary resistance (e.g. dilation of pre-capillary), the pressure post-that area will increase, which will favour extrusion. 

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7

Describe the Autoregulation of the blood vessel diameters. (one of the mechanisms that allow changes in blood flow to different organs)

Definition: the intrinsic tendency of an organ to maintain constant blood flow despite of changes in perfusion pressure.

 

In the presence of changes in perfusion pressure, you might acutely get increases or decreases in flow, but over time the blood vessel autoregulates so it goes back to approx the same. 

This autoregulatory response occurs in the absence of neural and hormonal influences and therefore is intrinsic to the organ, although thesse influences can modify the response. When perfusion pressure (arterial minus venous pressure, PA-PV) initially decreases, blood flow (F) falls because of the following relationship between pressure, flow and resistance:

When blood flow falls, arterial resistance (R) falls as the resistance vessels (small arteries and arterioles) dilate. Many studies suggest that metabolic, myogenic and endothelial mechanisms are responsible for this vasodilation. As resistance decreases, blood flow increases despite the presence of reduced perfusion pressure.

 

Muscle blood flow ~ perfusion pressure

  • Initially it's around 100mmHg and blood flow is around 2ml/min.
  • If the perfusion pressure increases, initially there will be an increase in flow, but after time, the flow returns to the similar level.
  • If you decrease the perfusion pressure, the flow intiitally falls but eventually will come back up. 

 

However if you drop your perfusion pressure enough (nothing goes in), the flow does drop off. 

 

The ability of an organ to display reactive hyperemia is similar to its ability to display autoregulation.

 

 

The link between blood flow and metabolism is demonstrated by phenomenon of autoregulation

  • As perfusion pressure (arterio-venous pressure difference) is increased, there is initial increase in blood flow which then returns towards the previous level (vice versa). This recovery of blood flow can occur within a few seconds.

The level at which blood flow is regulated typically depends on metabolic requirements of the tissue. Effectiveness of autoregulation varies between vascular beds:

  • Cutaneous circulation exhibits almost no autoregulation, while cerebral circulation is tightly autoregulated.
  • Even in circulations where autoregulation is well-developed, there are limits to range of perfusion pressures over which blood flow is regulated, e.g. in the cerebral circulation, autoregulation is maintained from 50 to 180mmHg.

 

Different organs display varying degrees of autoregulatory behavior. The renal, cerebral, and coronary circulations show excellent autoregulation, whereas skeletal muscle and splanchnic circulations show moderate autoregulation. The cutaneous circulation shows little or no autoregulatory capacity.

 

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8

If the perfusion pressure increases to 140mmHg, what happened to the diameter of the blood vessels such that flow was restored?

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The pre-capillary vessels constricted

9

Describe the concept of reactive hyperaemia

One of the examples of autoregulation is Reactive Hyperaemia

 

If you occlude a BV for a short period of time, when you release the BV, blood flow through the vessel increases for a period of time. And this is proportional to the duration of the occlusion. 

 

Reactive hyperemia is the transient increase in organ blood flow that occurs following a brief period of ischemia (e.g., arterial occlusion). Reactive hyperemia occurs following the removal of a tourniquet, unclamping an artery during surgery, or restoring flow to a coronary artery after recanalization (reopening a closed artery using an angioplasty balloon or clot dissolving drug).In general, the ability of an organ to display reactive hyperemia is similar to its ability to display autoregulation.

 

In this example, blood flow goes to zero during arterial occlusion. When the occlusion is released, blood flow rapidly increases (i.e., hyperemia occurs) that lasts for several minutes. The hyperemia occurs because during the period of occlusion, tissue hypoxia and a build up of vasodilator metabolites (e.g., adenosine) dilate arterioles and decrease vascular resistance. Then when perfusion pressure is restored (i.e., occlusion released), flow becomes elevated because of the reduced vascular resistance.

During the hyperemia, the tissue becomes reoxygenated and vasodilator metabolites are washed out of the tissue.  This causes the resistance vessels to regain their normal vascular tone, thereby returning flow to control. The longer the period of occlusion, the greater the metabolic stimulus for vasodilation leading to increases in peak reactive hyperemia and duration of hyperemia.  Depending upon the organ, maximal vasodilation as indicated by peak flow, may occur following less than one minute (e.g., coronary circulation) of complete arterial occlusion, or may require several minutes of occlusion (gastrointestinal circulation).  Myogenic mechanisms may also contribute to reactive hyperemia in some tissues. By this mechanism, arterial occlusion results in a decrease in pressure downstream in arterioles, which can lead to myogenic-mediated vasodilation.​

10

Describe the concept of Myogenic Hypothesis

  • Increased perfusion pressure increases vascular preesures throughout the circulation.
  • Increased transmural pressur eleads to veascular distension
  • Stretch elicits smooth muscle contraction. 

 

  • (so it says that if you have change in pressure in the BV and this pressure is sensed, it reflexively tries to hold the shape. It tries to maintain blood flow).
  • This isn't really responsible for re-distribution of blood flow (unlike autoregulation). 
    • The myogenic hypothesis (increase in pressure causes vasoconstriction) is offset by the vascular endothelium hypothesis (increases in pressure by shear stress causes release of NO- which causes it to vasodilate) 

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11

What are the different Hypotheses of Local Control/Autoregulation?

1) Myogenic Hypothesis/Control

  • Maintain blood flow (when it senses changes in stretch of BV)

2) Metabolic Hypothesis/Control

  • Predominantly responsible for skeletal and cadiac muscles. 
  • BV dilates as we go from normal resting conditions to active phase - to supply blood the muscles

3) Vascular Endothelial Control

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12

Describe the Metabolic Hypothesis

Predominantly responsible for skeletal and cadiac muscles. 

 

BV dilates as we go from normal resting conditions to active phase - to supply blood to the muscles

 

The reason why we get vasodilation is because you have metabolites (e.g. adenosine, K+, CO2, H+) which are released by exercising muscles, that act on the BV to cause it to vasodilate (to increase the supply to meet the demands of the muscle). 

 

Does not explain co-ordinated vasodilation throughout pre-capillary distribution circuit. 

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13

What are the effects of metabolites - Metabolic hypothesis.

 

What does this hypothesis not explain?

  • Cause vasodilation in nearby BV

 

  • Greatest in terminal pre-capillary vessels
  • Limited in post-capillary vessels
  • Does not explain coordinated vasodiatlion throughout pre-capillary distribution circuit. 

14

Describe the concept of Vascular Endothelium hypothesis

  • The vascular endothelium release Nitric Oxide which acts as a vasodilator
    • Increased blood flow increases shear stresses acting on the endothelium, which leads to the release of NO synthetase (and NO)
  • The myogenic hypothesis (increase in pressure causes vasoconstriction) is offset by the vascular endothelium hypothesis (increases in pressure by shear stress causes release of NO- which causes it to vasodilate) 

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15

Describe the distribution of sympathetic innervation

Each individual organ has different demand for blood/oxygen

When it works harder, it has mechanisms in place to demand more

 

Some organs (e.g. heart) this is easier, but others (e.g. kidney) that don't release as much metabolites, this is harder. So in these need more sympathetic innervation- these can redistribute blood.

 

Most smypathetics nerves are in the arterial and pre-capillary side. These change BV diameter. 

 

Increase in sympathetic drive to organs that do not require as much blood cause vasoconstriction. 

16

Describe how Sympathetic Adrenergic nerves work

If there's sympathetic activity, will this cause vasoconstriction or vasodilation?

  • Electrical activation of nerve terminal opens membrane Ca2+ channels leading to Ca2+ influx, so increased cytoplasmic Ca2+.
  • As a result, vesicles migrate to and fuse with junctional membrane, releasing their contents into intersynaptic cleft.
    • Noradrenaline (NA) is main neurotransmitter in sympathetic system
    • Dopamine b-hydroxylase and additional co-transmitters (e.g. adenosine triphosphate (ATP) and neuropeptide Y (NPY)) are also stored and released from vesicles.
  • Noradrenaline released into intersynaptic cleft binds to adrenoreceptors on VSM membrane.
    • a1 receptor is widely distributed in post-junctional membrane. This receptor is linked to G protein Gq, which activates phospholipase C, leading to increased secondary messengers (diacylglycerol and inositol triphosphate). As a result, Cytoplasmic/intracellular Ca2+ is increased.
      • Get greater contraction = vasoconstriction
    • Post-junctional a2 receptors are sparser than a1 receptors. This receptor is linked to G protein Gi, which inhibits adenylate cyclase, leading to decreased secondary messengers (cAMP). As a result, K+ will be removed and hyperpolarise the cell
      • = vasodilation. (this is diff to Nath's notes)
  • Depending on the amount of receptors, Sympathetic activity will result in vasoconstriction or vasodilation (and the amount you get)
    • But usually there's more a1 receptors.

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17

Describe the modulation of Adrenergic Neurotransmission

With the same amount of sympathetic drive to a given organ, you can either change the receptor levels (change amount of vasoconstriction/vasodilation you get) or change the circulating levels of inibitory and excitatory modulators.

 

Adrenergic neurotransmission is modulated by a number of regulatory receptors in nerve terminal membrane.

  • Adrenergic neurotransmission is modulated via NA autoreceptors (a2 receptors). Activation of these receptors closes Ca2+ channels in terminal membrane, inhibiting release of NA and stabilising its concentration in intersynaptic cleft.
  • A range of other factors also modulate adrenergic neurotransmission via presynaptic heteroreceptors.
    • Inhibitory factors include acetylcholine, adenosine, dopamine, histamine, prostaglandins E1 and E2.
    • Excitatory factors include angiotensin II and adrenaline.
      • If Angiotension II is amount, more norepinephrine is released. 

 

 

The role of co-transmitters in peripheral sympathetic nerve terminals is not fully understood. In some cases, they produce long-lasting actions that supplement effects of noradrenaline (the primary neurotransmitter).

  • For instance, it appears that neuropeptide Y has a similar excitatory function to noradrenaline. However, release occurs at relatively high levels of sympathetic activity and removal of this peptide is relatively slow.
  • Therefore, neuropeptide Y produces sustained excitation at high levels of sympathetic activation.

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18

How do angiotensin II and adrenaline affect the blood vessels?

It is an Excitatory factor 

If Angiotension II is around, the amount, more norepinephrine is released.

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19

Describe Cholinergic Nerves

Most VSM (vascular smooth muscle) is innervated solely by sympathetic adrenergic neurons, but some blood vessels are also innervated by parasympathetic cholinergic neurons that act as a vasodilator system.

These include pre-capillary vessels in heart, brain, face, tongue and urogenital tract.

  • Activation of these parasympathetic nerves leads to release of acetylcholine (ACh).
  • Circulating ACh binds to M3 muscarinic receptors in vascular endothelium. This stimulates synthesis and release of NO, causing vasodilation.
  • However, when endothelium is absent as result of vascular damage or removal, ACh acts directly on M2 muscarinic receptors in vascular smooth muscle, causing vasoconstriction.

20

Exogenous administration of adrenaline results in...

Exogenous administration of adrenaline (1g/min IV) at physiological levels produces similar vasoconstriction effects to noradrenaline in most vascular beds. However, it causes vasodilation in skeletal muscle and splanchnic circulations.

  • Increased blood flow of skeletal muscle, spleen.
  • Decreased blood flow of skin, kidney.

21

Describe the effects of circulating catecholamines and explain why this is seen

Mechanisms Of Noradrenaline And Adrenaline

Exogenous administration of noradrenaline (1-2g/min IV) causes widespread vasoconstriction with exceptions of coronary and cerebral circulations.

  • Decreased blood flow of skeletal muscle, spleen, skin, kidney.

 

Exogenous administration of adrenaline (1g/min IV) at physiological levels produces similar vasoconstriction effects to noradrenaline in most vascular beds. However, it causes vasodilation in skeletal muscle and splanchnic circulations.

  • Increased blood flow of skeletal muscle, spleen.
  • Decreased blood flow of skin, kidney.

 

Explanation:

These are explained by existence of b2 and a adrenergic receptors in circulation, which have different affinities for noradrenaline and adrenaline.

  • b2 receptors are coupled via G protein Gs to cAMP system. Therefore, b2 agonists produce vasodilation. On basis of effects of exogenous administration outlined above, it can be inferred that:
    • a as adrenergic receptors are distributed in pre- and post-capillary vessels in most organs.
    • b2 as adrenergic receptors are present in pre-capillary vessels only in skeletal muscle and splanchnic circulations.

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22

Exogenous administration of noradrenaline results in...

Exogenous administration of noradrenaline (1-2g/min IV) causes widespread vasoconstriction with exceptions of coronary and cerebral circulations.

  • Decreased blood flow of skeletal muscle, spleen, skin, kidney.

23

 

  • a receptors have affinity of ____ = _____ >> _____
  • b2 receptors have affinity of _____ > _____ >> ______

Potency series for endogenous catecholamines (noradrenaline and adrenaline) and synthetic catecholamine (isoprenaline) are:

  • a receptors have affinity of adrenaline = noradrenaline >> isoprenaline
  • b2 receptors have affinity of isoprenaline > adrenaline >> noradrenaline

24

Describe the Neuro-Humaoral Control (and local factors) on the skeletal muscles during exercise.

Skeletal Muscle Circulation

Local Control

There is an evident link between metabolism and blood flow in skeletal muscle circulation. This circulation exhibits precise autoregulation (maintains a relatively constant steady blood flow over a wide range of perfusion pressures).

 

Neuro-Humoral Control (and Local Factors)

Skeletal muscle circulation has dense sympathetic adrenergic innervation. At rest, it is a powerful controller of vascular resistance in circulation and can effectively "shut down" muscle blood flow.

 

With exercise, there is a substantial fall in vascular resistance in skeletal muscle circulation. At moderate and high levels of exertion, sympathetic adrenergic activity is totally ineffective in face of exercise-induced vasodilation. Instead, increased perivascular concentration of vasodilator metabolites controls effects:

  1. It relaxes vascular smooth muscle (vasodilation) either directly or via the endothelium
  2. It also inhibits sympathetic adrenergic neurotransmission.

These potent metabolic effects are complemented by a range of further mechanisms.

  1. In addition to sympathetic adrenergic innervation, resistance vessels in some species are innervated by sympathetic cholinergic fibres, which are thought to be activated in anticipation of exercise.
  2. There is also a mixed population of a and b2 adrenoreceptors in skeletal muscle resistance vessels.
  3. Increased circulating adrenaline in exercise will also sustain vasodilation by acting on precapillary b2 receptors.
  4. Histamine and other autocoids are also released in exercise, which act to dilate pre-capillary vessels and also inhibit sympathetic neurotransmission.

25

Describe the anatomy of the skin circulation

Anatomy

Cutaneous circulation is characterised by low capillary densities, and large numbers of superficial arterio-venous shunt vessels (significantly greater in cross-sectional dimension).

 

These shuts function as heat exchangers. The following discussion relates to regulation of blood flow supplied to these AV shunts.

26

Describe the Neuro-Humaoral Control (and Local Factors) of skin circulation when at rest and when exercising

Local Control

Link between metabolism and blood flow in cutaneous circulation is small (even at rest, blood flow is greater than tissue requirements). Therefore, autoregulation is poorly developed in the skin.

 

Neuro-Humoral Control (and Local Factors)

Cutaneous circulation is densely innervated (heavily influenced) by sympathetic adrenergic system. Note that only a adrenergic receptors are present.

However, it is also affected by local factors (increase cutaneous blood flow in exercise and hence facilitate heat loss):

  • Affinity of a receptors for NA decreases as temperature rises, vice versa. Therefore, local warming will lead directly to increased skin blood flow.
  • Sympathetic cholinergic activation of sweat glands results in release of enzyme kallikrein, which activates kinin cascade.
  • Bradykinin and lysylbradykinin dilate pre-capillary vessels, constrict post-capillary vessels, increase capillary permeability.

In mild to moderate exercise, firing rates for sympathetic nerves that supply resistance vessels in cutaneous AV shunts decline. This is in contrast with skeletal muscle circulation, where there is increased sympathetic activation, but is ineffective in presence of metabolism.

27

In the skin, only _____receptors are present

only a adrenergic receptors are present.

28

Contrast the changes in circulation between skin and skeletal muscles during mild exercise

In mild to moderate exercise, firing rates for sympathetic nerves that supply resistance vessels in cutaneous AV shunts decline. This is in contrast with skeletal muscle circulation, where there is increased sympathetic activation, but is ineffective in presence of metabolism.

29

Describe the Neuro-Humaoral Control (and Local Factors) of Cerebral circulation

Local Control

In cerebral circulation, there is a tight linkage between metabolism and blood flow. The cerebral circulation exhibits very precise autoregulation over perfusion pressure range of 60-180mmHg.

Autoregulation fails when perfusion pressure falls below 50mmHg, and oxidative metabolism in brain may be impaired for perfusion pressures of 40mmHg and less.

 

Neuro-Humoral Control (and Local Factors)

Although total cerebral blood flow remains remarkably constant through range of different daily activities, there can be major regional variations in distribution of blood flow within brain.

 

Cerebral blood flow is dominantly regulated by local factors. Perivascular pH and PCO2, especially, as well as PO2 and [K+] are important vasodilator metabolites in matching metabolism and blood flow in cerebral circulation.

  • Increased PaCO2 above normal level of 40mmHg lead to increased cerebral blood flow (max. 2 resting level with severe hypercapnia), while reduced PaCO2 leads to reduced cerebral flow (min. 1/4 resting level with extreme hypocapnia).
  • There is initially little change in cerebral blood flow when PaO2 is reduced from normal 100mmHg. However, when PaO2 drops below 50mmHg, cerebral blood flow increases (max. 2 resting level with severe hypoxia).

 

Cerebral vessels receive both symp. and parasymp. innervation. Innervation densities varies widely but generally sparse.

  • Sympathetic stimulation can produce substantial transient responses, but role of neural control in regulation of cerebral blood flow remains a matter of debate.
  • Circulating catecholamines have little effect in cerebral circulation, since they do not normally penetrate tight endothelial junctions of cerebral capillaries.

 

Finally, it is important to recognize that cerebral circulation may be markedly affected by accumulation of interstitial fluid volume. This results in increased intracranial pressure, which may reduce cerebral perfusion.

  • Cerebral circulation may be viewed as being contained in a highly incompliant compartment. Skull imposes a completely rigid constraint.
  • As a result, small increases in interstitial volume can lead to substantial increases in intracranial pressure (tissue pressure Pe becomes bigger, potentially exceeding capillary pressure Pi).

This impact very directly on cerebral blood flow

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