What is the role of the circulation?
To transport blood around the body -> to deliver O2, nutrients and signalling molecules, remove CO2 and metabolites and to regulate temperature
How is flow achieved in the circulation?
By action of muscular pump (heart) which generates a pressure gradient that propels blood through a network of tubes (blood vessels)
What does the circulation consist of?
2 pumps -> L/RV which are physically coupled and pump through the systemic and pulmonary circulations respectively
What is diffusion crucial for and when is it effective?
Crucial for movement of materials through tissues and is only effective over short distances so a capillary needs to be 10micrometres from every cells, necessitating a highly branched structure
How is the circulation designed?
Veins have high capacitance and act as a reservoir -> large amount of volume of the blood is stored there
How are arteries, capillaries and veins structured to increase efficiency of their respective roles?
Large arteries act as conduits and dampening vessels (elastic); Small arteries/arterioles have extensive SM in their walls to regulate their diameters and the resistance to blood flow; Capillaries have very thin walls to facilitate transport and diffusion; Veins and venules are highly compliant and act as a reservoir for blood volume
What are the relative cross-sectional areas and volumes in the circulation?
The capillaries have the larges cross-sectional area as they need a larger SA for exchange -> which is their main function. Venules and veins have the largest relative volume of blood contained within the vessels as their main function is to act as a reservoir and hold blood
Why does blood flow?
Due to blood pressure -> force that drives the circulation
What is Darcy's law for current flow?
Delta P = Q*R
What is the determinant of mean blood pressure?
MBP = CO * PVR -> NB: assumes steady flow, whicih doesn't occur due to intermittent pumping of heart, vessels are rigid and RA pressure is negligible
How is the regulation of flow achieved physiologically?
Variation in resistance while BP remains relatively constant
How does the pressure vary throughout the circulation?
Pressure falls across the circulation due to viscous pressure losses -> small arteries and arterioles present most resistance to flow as they can reduce their diameter or increase it
Which variables does the resistance to blood flow depend on?
Fluid viscosity (not fixed but under most physiological conditions is constant), Length of tube (fixed) and inner radius of tube (variable!!! and MOST IMPORTANT) -> importance of arterial diameter as a determinant of resistance -> relatively small changes in vascular tone can produce marked changes in flow
How can resistance to flow change in physiological circumstances?
Exercise can change the distribution of blood flow HUGELY, by altering arteriolar radius
What is Laminar flow?
Flow of fluid when each particle of the fluid follows a smooth path; flowing in layers or streamlines, paths which don't interfere with one another: VELOCITY is constant at any one point
What are the 2 types of flow that can occur in vessels?
Laminar and turbulent flow
What is turbulent flow?
Irregular flow characterised by tiny whirlpool regions and associated with pathophysiological changes to the endothelial lining of the blood vessels -> VELOCITY is NOT constant at every point -> pathophysiology changes to the endothelial lining occur due to changes in shear stress
What is shear stress?
There are adhesive forces between fluid and surface, so velocity of layers increases as distance from wall increases -> the shear rate is the velocity gradient at any point and the shear stress is the shear rate multiplied by the viscosity
What does laminar shear stress cause in the endothelial cells?
High shear stress (laminar flow) promotes endothelial cell survival and quiescence, cell alignment in the direction of flow and secretion of substances that promote vasodilation and anticoagulation
What does disturbed shear stress cause in the endothelial cells?
Low shear stress or changing shear stress direction (turbulent flow), promotes endothelial proliferation and apoptosis, shape change, secretion of substances that promote vasoconstriction, coagulation and platelet aggregation
How is blood pressure taken?
Takes advantage of turbulent flow -> Korotkoff sounds (SBP is start of sounds and DBP is end of sounds) and most commonly measured with a cuff on the upper arm
How is pulse pressure measured?
SBP - DBP
How is MBP measured?
DBP + 1/3 PP
Why does the aortic pressure not fall when the ventricular pressure falls?
Once the aortic valve closes, ventricular pressure falls rapidly but aortic pressure only falls slowly in diastole -> due to elasticity of aorta and large arteries which act to buffer the change in pulse pressure -> elasticity of vessel is related to compliance
What is the Windkessel effect?
During ejection blood enters the arteries faster than it is removed, so 40% of SV is stored by the elastic arteries -> when the aortic valve closes and ejection ceases, due to the recoil of elastic arteries, pressure falls slowly and there is diastolic flow in the downstream circulation -> dampening effect
What happens if arterial compliance decreases (with age)?
Dampening effect of Windkessel is reduced and pulse pressure increases
What is the effect of pressure on the walls of vessels?
Transmural pressure causes tension force in the wall that can be described by Laplace's relationship T=P*R and circumferential stress is Tension force/wall thickness -> Maintained high circumferential stress causes vessel distension
What is an aneurysm?
Over prolonged period, vessel walls weaken causing balloon-like distension -> if aneurysm forms in a blood vessel wall, radius of vessel increases (Laplace) -> so for same internal pressure, inward force exerted by muscular wall must also increase BUT muscle fibres have weakened so force needed can't be produced so aneurysm will expand and often ruptures -> same in diverticulitis
What is the difference in compliance properties of arteries and veins?
Compliance depends on vessel elasticity -> venous compliance is 10-20x greater than arterial compliance at low pressures -> increasing SM contraction, decreases venous volume and increases venous pressure -> most blood volume is stored in veins
What is the problem with standing - venous compliance?
Standing increases hydrostatic pressure in legs to 80mmHg due to gravity -> blood transiently pools in the veins due to their compliance and reduces venous return to the heart which reduces CO and BP if there were no compensatory response
What is the main effect of gravity in the circulation?
Extent to which gravity increases hydrostatic pressure in vessels varies with height but ~= 100mmHg -> at any particular location, gradient of pressure from large artery to capillary to vein is maintained so flow still occurs in the same way -> major effect is on the distensible veins in the leg and the volume of blood contained in them
Why don't we faint when standing?
Standing causes: 1)Activates SNS: to constrict venous SM and stiffen veins, constrict arteries to increase resistance and maintain BP, increase HR and SV, maintain CO; 2) myogenic venoconstriction to stiffen veins (response to elevated venous pressure); 3) use of muscle and resp pumps to improve venous return -> BUT cerebral blood flow falls on standing -> failure causes syncope
What are the 2 pumps used by the venous system?
Skeletal muscle pump and respiratory pump
What is the function of the skeletal muscle pump?
Contract muscles, to push blood back up, with the valves in the veins preventing backflow of blood, so the blood travels up the veins
What is the function of the respiratory pump?
Increasing breathing, which pulls diaphragm down, decreasing the pressur ein the thorax, so more blood can enter the thorax via the IVC
What are other problems with standing?
Varicose veins -> incompetent valves cause dilated superficial veins in the leg. Oedema in feet -> prolonged elevation of venous pressure, even with intact compensatory mechanisms
What is the vascular endothelium?
Innermost layer -> 1 cell thick, very small around all the vasculature -> acts as blood-vessel interface
What is the physiology of the CVS?
Generate flow, stabilise pulsatile flow, facilitate gas and solute exchange, maintain unidirectional flow
What is the function of the vascular endothelium?
Vascular tone management (secretes and metabolises vasoactive substances), thrombostasis (prevents clots forming/molecules adhering to wall), absorption and secretion (allows passive/active transport via diffusion/channels), barrier (prevents atheroma development), growth (mediates cell proliferation)
How do we control vascular function?
Circulation -> hormones (change amount of constriction); drugs (ACE inhibitor); shear stress. Nervous -> NT
What are the 5 mediators of vascular endothelial function?
NO, prostacyclin (PGI2), thromboxane A2 (TXA2), Endothelin-1 (ET-1), Ang II
What is the effect of NO on smooth muscle and platelets (myocytes = EXTRA)?
SM: Relaxation and growth inhibition. Platelets: Inhibits aggregation [M: increased blood flow, increased contractility]
What is the effect of PGI2 on smooth muscle and platelets (myocytes = EXTRA)?
SM: Relaxation and growth inhibition. Platelets: Inhibits aggregation [M: increased blood flow]
What is the effect of TXA2 on smooth muscle and platelets (myocytes = EXTRA)?
SM: Contraction Platelets: Activation, stimulates aggregation [M: reduced blood flow]
What is the effect of ET-1 on smooth muscle and platelets (myocytes = EXTRA)?
SM: contraction, stimulation of growth [M: reduced blood flow, increased contractility]
What is the effect of Ang II on smooth muscle and platelets (myocytes = EXTRA)?
SM: Contraction and stimulation of growth [M: reduced blood flow, remodelling and fibrosis]
How is vascular tone kept constant - which factors have an effect on vasodilation/constriction?
Vasodilation - NO, ET-1, PGI2 Vasoconstriction - TXA2, ET-1, Ang II
How is NO produced and how does it cause its effects in the vascular endothelium?
ACh (or something) binds to a G=protein coupled receptor, which activates an PLC, which converts PIP2 into DAG and IP3. IP3 causes influx of Ca into the cytosol from the ER, which activates eNOS. eNOS converts L-arginine and O2 into L-citruline and NO, which diffuses into VSMC. NO upregulates Guanylyl cyclase, which converts GTP to cGMP, which activates Protein Kinase G which triggers relaxation -> NB: NO has a short half life, so acute effects produced
What is DAG, IP3, PIP2, eNOS, PLC?
DAG - diacylglycerol, IP3 - inositol triphosphate, ***PIP2 - phosphatidylinositol 4,5-bisphosphate, eNOS - endothelial NO synthase PLC - phospholipase C
What are the 2 things that upregulate eNOS?
Ca2+ in the cytoplasm and shear stress
What are the techniques that can assess the healthiness of blood vessels - NO testing mainly?
Flow-mediated vasodilation and endothelium-dependent vasodilation
How is arachidonic acid (AA) synthesised and what effects does it have?
Phospholipase A2 converts P/L into AA, which forms EITHER leukotrienes via lipooxygenase OR PGH2 via COX1 and 2 enzymes. PGH2 is converted into EITHER prostacyclin via prostacyclin synthase OR TXA2 via thromboxane synthase OR PGD2, PGE2, PGF2 which are associated with pain, fever and inflammation
What is another way of making Arachidonic Acid?
DAG converted by DAG lipase into AA, which then continues down the AA cascade (COX)
What happens when PGI2 is produced in the endothelial cell?
It either binds to PGI2 receptor and VSMC or goes into the lumen. When bound to receptor (IP), it activate adenylyl cyclase converting ATP to cAMP, which activates PKA which leads to relaxation
What happens when TXA2 is produced in the endothelial cell?
It binds to platelets (TPalpha) or VSMC (TPdelta) with receptor -> in VSMC it leads to PLC to move across membrane, so PIP2-> IP3, which leads to Ca influx, so more contraction occurs as cross-bridge forming increases, so cells shorten In Platelets -> leads to activation of platelet, arachidonic acid in platelets synthesised to TXA2, which is then released and activate the platelet cascade, as more platelets are activated by TXA2
How is ET-1 formed and what happens when ET-1 is produced in the endothelial cell?
ET-1 is derived from nucleus from endothelial cell -> Big ET-1 converted by endothelin converting enzyme on membrane of endothelial cell, into ET-1, which comes out of the cell, into interstitial space and can bind to ETA/B receptors on VSMC which are attached to PLC, so PIP2 into IP3, which causes contraction (due to influx of Ca) -> STRONGER EFFECT (principle). If ET-1 binds onto ETB receptor on endothelial cell, it leads to upregulation of eNOS, which leads to NO synthesis, which causes relaxation of the muscle
What are some ET-1 synthesis antagonists?
PGI2, NO, ANP, heparin, HGF, EGF
What are some ET-1 synthesis agonists?
Adrenaline, ADH, Ang II, IL-1
How is Ang II synthesised?
Liver secretes Angiotensinogen (inactive) which is converted by the kidney's enzyme Renin into AngI, which then uses ACE (located on inside of blood vessels in lungs and kidneys) to convert Ang I > Ang II
What are the 5 roles of Ang II?
Increase ADH, aldosterone secretion and tubular Na reabsorption -> increased water retention. Excites SNS and causes arteriolar vasoconstriction -> increased vascular secretion. OVERALL effect = increased BP
What are the AngII pathways?
Ang II binds to AT1 receptors (VSMC) which activate PLC, so PIP2 > IP3 causing contraction; also binding to AT1 which activates SRC, which causes mainly growth with contraction as a minor effect. Bradykinin is broken down by ACE, which when active binds to B1 receptors on endothelial cells, which activates PLC, converting PIP2 to IP3, which releases NO, which leads to relaxation
What are the additional effects of AngII?
How would we cause vasodilation?
Increase NO bioavailability either by stimulating production of NO or by donating ready to use NO, or by enhancing the effects of NO
How do NO-donors differ in mechanism from NO synthesised in endothelial cells?
NO upregulates guanylyl cyclase converting GTP to cGMP which then activates PKG which causes relaxation -> BUT body has safety mechanism called phosphodiesterase which converts cGMP to GMP, stopping the relaxing effect -> VIAGRA blocks phosphdiesterase, so enhancing the vasodilatory effects of NO
What is the effect of low-dose aspirin?
Aspirin irreversible inhibition of the COX enzymes -> PGI2 - predominantly produced in endothelial cells, so even though COX enzymes are deactivated, the cell can produce some more. TXA2 -> because platelets don't have a nucleus they can't remake COX, so it reduces the amount of TXA2 in the blood
What does aspirin do to COX enzymes?
COX-1 : aspirin acetylation, inactivating enzyme. COX-2: aspirin acetylation switches its function (generating protective lipids) -> causes irreversible inhibition of COX enzymes, other NSAIDs cause reversible inhibition; COX-2 specfic inhibitors cause reversible inhibition of COX-2 isoforms only
Where is cytosolic Ca2+ moved in the cell?
Red circles are where Ca moves out, and purple where Ca moves in ->
What is the role of Ca?
VGCC mediate Ca2+ influx in response to membrane depolarisation -> Ca acts as intracellular messenger in transduction pathways; regulates intracellular processes such as actin-myosin interaction, membrane transport, neurotransmission, gene expression -> activity essential to couple electrical signals in the cell surface to physiological events in cells
What do medications that interrupt Ca do?
Block Ca influx, vasodilation reduces afterload, negative ionotropic effect, prevent coronary artery vasospasm, which makes them very useful in treatment of variant angina
What do ACE inhibitors and AngII receptor blockers block?
What are the side effects of drugs?
Body often uses same chemical to regulate multiple processes and there is interaction between different systems in the body so drugs aren't always tissue specific, so 2 people taking the same drug can have varied experiences
Is aspirin an anticoagulant?
No. It is an an anti-platelet; warfarin is an anticoagulant