The blood flow to a particular tissue is regulated at the minimal level that will supply the tissue's requirements. This ensures that the tissues are always adequately supplied, whilst keeping the workload on the heart to a minimum. Acute control of local blood flow is achieved within seconds to minutes by changes in local vasodilator/vasoconstriction of the arterioles and small arteries effected through relaxation/contraction of the vascular smooth muscle. The state of contraction of the vascular smooth muscle is referred to as vascular tone. The arteries are normally maintained in a partial state of contraction (vasomotor tone) by the continual firing of nervous impulses from the vasomotor centre.
The vascular endothelium lining the lumen can modulate vascular tone by the synthesis and release of potent vasorelaxant and vasoconstrictor substances. Release of these substances is usually balanced in favour of vasodilators, notably epithelium-derived relaxing factor, prostacyclin and endothelium-derived hyperpolarizing factor. Epithelium-derived relaxing factor has been identified as the nitric oxide radical (NO*) (Palmer et al., 1987; Ignarro et al., 1987), which is formed within endothelial cells by the oxidative deamination of L-arginine (Palmer et al., 1988). The enzyme responsible, endothelial constitutive nitric oxide synthase, requires tetrahydrobiopterin as a co-factor and is regulated by protein kinase C. Inhibition of protein kinase C increases the expression of the synthase, resulting in an increased synthesis of nitric oxide (Ohara et al., 1995). The synthesis/release of nitric oxide is mediated directly by shear stress on the endothelial cells caused by the viscous drag that results from an increase in blood flow. There is a constant basal release under the stimulus of pulsatile blood flow. Nitric oxide is also synthesized and released in response to a large number of agents which activate endothelial surface receptors. These agents include local mediators (e.g. bradykinin, histamine and substance P), ADP released by aggregating platelets, and thrombin formed after activation of the coagulation cascade. The hormone noradrenaline, acting via en-dothelial a2 adrenergic receptors, can also cause the release of nitric oxide. The calcium ionophore A23187 is an endothelium-dependent vasodilator that acts independently of a membrane receptor. With some agents, relaxation may be limited to certain animal species (Furchgott & Vanhoutte, 1989).
The nitric oxide generated in the endothelium diffuses to the underlying smooth muscle where it stimulates guanylyl cyclase to produce cyclic guano-sine monophosphate (cyclic GMP). Relaxation of the smooth muscle may be effected through a cyclic GMP-dependent protein kinase which controls the phosphorylation and dephosphorylation of myosin light chains (Luscher, 1991). Nitric oxide and prostacyclin act synergistically to cause relaxation because two different second messengers, cyclic GMP and cyclic AMP, are involved. Endothelium-derived hyperpolarizing factor may facilitate relaxation and attenuate the responsiveness of the smooth muscle to certain vasoconstrictor hormones (Luscher, 1990). A simplified scheme of nitric oxide-mediated vascular relaxation in normal blood vessels is shown in Fig. 4.13.
Treatment of isolated segments of rabbit artery with pharmacological concentrations of acetylcholine causes nitric oxide-mediated vasodilation through the activation of muscarinic receptors on the endothelial cells. If the endothelial layer is removed from the segments, thereby removing the source of nitric oxide, the normal vasodilator response to acetylcholine is replaced by vasoconstriction resulting from the direct effect of this agent on the smooth muscle (Furchgott & Zawadski, 1980). This discovery has been regarded as an indication of a pathological mechanism rather than a physiological one because acetylcholine, as a neurotransmitter released from the periarterial nerves, is unlikely to diffuse all the way through the medial muscle coat before acting on endothelial cells. However, Burnstock (1987) demonstrated ultrastructural localization of choline acetyltransferase in endothelial cells in rabbit cerebral, femoral and mesenteric arteries, indicating that endothelial cells can synthesize acetylcholine and store it.
Hypercholesterolaemia and atherosclerosis profoundly impair endothelium-dependent arterial relaxation as demonstrated, for example, in the aortas of rabbits (Habib et al., 1986; Verbeuren et al., 1986), the iliac arteries of monkeys (Freiman et al., 1986) and the coronary arteries of pigs (Shimokawa & Vanhoutte, 1989) and humans (Ludmer et al., 1986; Bossaller et al., 1987; Förstermann et al., 1988a). Depletion of tetrahydrobiopterin, an essential cofactor for nitric oxide synthase, causes impaired nitric oxide generation (Schmidt et al., 1992). Stroes et al. (1997) speculated that decreased nitric oxide-dependent va-sodilation in hypercholesterolaemia could be related to a relative deficiency of tetrahydrobiopterin, resulting in impaired nitric oxide synthase activity. They then showed that tetrahydrobiopterin did indeed restore the disturbed nitric oxide-dependent vasodila-tion in patients with familial hypercholesterolaemia, at a stage when macrovascular disease had not yet occurred.
Ludmer et al. (1986) showed that the hypercontrac-tility of diseased coronary arteries might be attributable to an abnormal vascular response to acetylcho-line. Graded concentrations of acetylcholine and, for comparison, the endothelial-independent vasodilator glyceryl trinitrite were infused into a coronary artery of eight patients with advanced coronary stenoses (>50% narrowing), six patients with mild coronary atherosclerosis (<20% narrowing), and four control subjects with angiographically normal coronary arteries. Acetylcholine produced dilation in each of the normal coronary arteries. In contrast, all eight of the arteries with advanced stenosis and five of the six vessels with minimal disease showed dose-dependent acetylcholine bradykinin
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