Physiology for MRCEM Primary

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Cardiovascular physiology

Blood vessel physiology

[box type=”download”] Peripheral vascular physiology I Basis of vasoconstriction  Appreciation of the role of G-protein mediated changes in intracellular calcium levels  Implications of calcium-channel blocking drugs upon vasoconstriction  Note: detailed knowledge of the vasoactive enzyme pathways is NOT required Endothelial function  Its role as a source of vasoactive mediators  Stimuli to endothelial secretion [/box]


Three layers:
an inner intima (tunica intima) consisting of a thin layer of endothelial cells;
a thick media (tunica media) containing smooth muscle and elastin filaments that provide elastic properties;
an outer adventitia (tunica adventitia) consisting of fibroblasts and nerves embedded in collagenous tissue.
The layers are separated by inner and outer elastic lamina.
In large vessels, the adventitia contains a network of blood vessels called the vasa vasorum (vessel of vessels) supplying the smooth muscle.
Veins have a thinner media than arteries (less smooth muscle).
Vascular smooth muscle cells are orientated in a spiral fashion, the lumen therefore narrows as they contract. Cells are connected by gap junctions, allowing electrical coupling and depolarization to spread from cell to cell.

Capillaries and the smallest venules have a single layer of endothelial cells supported by a basal lamina containing collagen on the outside.
The luminal surface is covered by a glycoprotein network called the glycocalyx.
There are three basic types of capillary, varying in permeability.
Continuous capillaries have a low permeability(tight junctions), found in skin, lungs, central nervous system and muscle.
Fenestrated capillaries (less tight junctions) have punctured endothelial cells (fenestrae); they are therefore much
more permeable. They are found in endocrine glands, renal glomeruli and intestinal villa.
Discontinuous capillaries are found in bone marrow, liver and spleen, and have gaps large enough for red blood cells to pass through.

Regulation of function and excitation–contraction coupling

Most vasoconstrictors bind to receptors and cause a G-protein-mediated rise in intracellular [Ca2+] leading to contraction.
Important vasoconstrictors include endothelin-1, angiotensin II and the sympathetic transmitter noradrenaline (norepinephrine).

Ca2+ release.
Binding to a receptor activates phospholipase C, which generates the second messengers inositol trisphosphate (IP3) and diacylglycerol (DAG) from membrane phospholipids. IP3 activates receptors on the sarcoplasmic reticulum (SR) causing Ca2+ release into the cytoplasm; this may itself activate Ca2+ sensitive Ca2+ release channels (ryanodine receptors, RyR) and further Ca2+ release.
Emptying of the SR initiates store operated or capacitative Ca2+ entry.

Ca2+ entry.
Vasoconstrictors most commonly cause depolarization, which activates Ca2+ entry via L-type
voltage-gated Ca2+ channels as in cardiac muscle. Vascular smooth muscle tend to generate graded depolarization instead of action potentials, allowing graded entry of Ca2+.
Receptor-operated channels (ROC) may also be activated, some by DAG, through which both Ca2+ and Na+ can enter the cell; the latter contributes to depolarization.
Emptying of SR Ca2+ stores is detected by STIM (stromal interaction molecule) which activates store-operated channels (SOC) such as ORAI in the membrane, causing capacitative Ca2+ entry.
Many agonists also cause Ca2+ sensitization of the contractile apparatus, i.e. more force for same Ca2+.
This is mediated by G-protein-mediated activation of Rho kinase, although protein kinase C, which is activated by DAG, may also be involved.

Ca2+ removal and vasodilatation.
Ca2+ is pumped back into the SR (sequestrated) by the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA). Ca2+ is also removed from the cell by a plasma membrane Ca2+ ATPase (PMCA) and Na+–Ca2+ exchange.
Most endogenous vasodilators cause relaxation by increasing cyclic guanosine monophosphate (cGMP) (e.g. nitric oxide, NO) or cyclic adenosine monophosphate (cAMP) (e.g. prostacyclin [prostaglandin I2, PGI2]; β-adrenergic receptor agonists).
These second messengers act via protein kinase G (PKG) or protein kinase A (PKA), respectively.
Both PKG and PKA lower intracellular Ca2+, partly by stimulating SERCA and PMCA, and partly by hyperpolarizing the membrane (i.e. so voltage-gated Ca2+ entry is inhibited).
L-type Ca2+ channel blocker drugs, such as verapamil or dihydropyridines, are clinically effective vasodilators.

The endothelium.
Plays a crucial role in the regulation of vascular tone.
In response to substances in the blood or changes in blood flow, it can synthesize vasodilators, including NO and prostacyclin, as well as potent vasoconstrictors, such as endothelin-1 and thromboxane A2 (TXA2).
NO is synthesized by the endothelial nitric oxide synthase (eNOS) from L-arginine by factors that elevate intracellular Ca2+, including local mediators such as bradykinin, histamine and serotonin, and some neurotransmitters (e.g. substance P).
Increased flow (shear stress) also stimulates NO production, and additionally activates prostacyclin synthesis. The basal production of NO continuously modulates vascular resistance, as it has been found that inhibition of eNOS causes the blood pressure to rise.
NO also inhibits platelet activation and thrombosis.
Endothelin-1 is an extremely potent vasoconstrictor peptide which is released from the endothelium in the presence of many other vasoconstrictors, including angiotensin II, antidiuretic hormone (ADH;
vasopressin) and noradrenaline, and may be increased in disease and hypoxia.
As endothelin receptor blockade causes a fall in the peripheral resistance, it seems to contribute to the
maintenance of blood pressure.
The eicosanoids prostacyclin and TXA2 are synthesized by the cyclooxygenase pathway from arachidonic acid, which is made from membrane phospholipids by phospholipase A2. In most vessels
prostacyclin is most important.