Although the importance of the endothelium as a nonthrombogenic surface has been known for some time, its role in modulating arterial tone was unrecognized until the early 1980s, when Furchgott and Zawadski187 observed that this cell type was obligatory for the relaxation response to acetylcholine. Although cholinergic vasodilation in vivo had been recognized, its mechanism was difficult to study because the event rarely could be reproduced in vitro. In their landmark paper, Furchgott and Zawadski187 reported that endothelial denudation abolished relaxation to acetylcholine and hypothesized that cholinergic stimulation led to the release of a substance that relaxed VSM. This compound, initially called endothelium-derived relaxing factor (EDRF), was subsequently shown to be NO. NO is a gas produced during the conversion of the amino acid L-arginine into L-citrulline by the enzyme NO synthase.188 In addition to its vasodilatory actions, NO is now known to be an important cytotoxic molecule used by the immune system, a neurotransmitter, a modulator of cell division,1^9 and, as discussed earlier, a modulator of myocardial function and energy metabolism.
It is now clear that the endothelium performs a variety of chemo- and mechanotransduction functions and releases a host of vasoactive molecules in response to physical and chemical stimulation.180 In addition to NO, the latter include ET-1190 and dilator and constrictor prostaglandins (e.g., prostacyclin and thromboxane, respectively). There is also experimental evidence for a non-NO factor that hyperpolarizes VSM. This substance has been termed endothelium-derivedhyperpolarizing factor (EDHF).191 Endothelial secretions diffuse to adjacent VSM to activate a variety of signal-transduction mechanisms that alter intracellular concentrations of cyclic AMP (induced by prostaglandins), cyclic GMP (via NO), phospholipase C (ET-1), and membrane potential (EDHF). Release of endothelium-derived vasoactive molecules is controlled by a variety of factors, both chemical and physical. The endothelium is exposed to much higher levels of shear stress than most other tissues. Shear is thought to be an important stimulus for a number of endothelial events, including hyperpolarization (opening of K channels), Ca influx, up- and down-regulation of mRNA for many proteins (e.g., adhesion molecules, tissue plasminogen activator, heat shock proteins), induction of G proteins and a number of kinases (protein kinase C, mitogen activated protein kinase), cytoskeletal rearrangement, and release of cytokines and growth factors.176 There is also evidence that shear stress modulates arterial growth and remodeling through an endothelium-dependent mechanism.192 Altered small artery endothelial function (most often characterized by diminished release of vasodilator substances) has been reported in vascular diseases such as hypertension and diabetes.193,194 In larger arteries, abnormal flow patterns (turbulence, eddy currents) associated with reduced shear stress may lead to metabolic derangements in endothelial function and accelerate the development of atherosclerotic lesions.
Most arteries and veins receive direct sympathetic innervation. Sympathetic tone contributes to maintenance of arterial and venous pressure under normal and stressful conditions. Sympathetic efferent activity is determined by a complex interaction of neurons in the spinal cord, medulla, pons, hypothalamus, limbic system, and portions of the forebrain and, as discussed earlier, by feedback signals arising from cardiovascular mechano- and chemoreceptors localized in discrete baroreceptor centers in the carotid sinuses, aortic arch, and the heart. The two central nervous system (CNS) areas that appear to be of principal importance in regulating sympathetic outflow are the nucleus tractus solitarius (NTS) and the rostral ventral lateral medulla (RVLM). The influence of the NTS on the RVLM is inhibitory: In animals, bilateral lesions lead to malignant hypertension. Sympathetic denervation produces widely varying effects on organ blood flow. Cerebral and coronary circulations are virtually unaffected, most likely as a result of the dominance of intrinsic autoregulatory mechanisms, whereas denervation of the skin or skeletal muscle produces substantial increases in blood flow. During intense sympathetic activation, large amounts of epinephrine (and, to a lesser extent, norepinephrine) are released from the adrenal medulla in response to activation of sympathetic preganglionic afferents. Blood pressure increases markedly, and significant redistribution of CO occurs (e.g., simultaneous increased perfusion of skeletal muscle and decreased splanchnic flow). Moreover, stimulation of the venous circulation increases venous return, thereby augmenting CO.
The efferent fibers of the cranial division of the parasympthetic system innervate the blood vessels of the head and viscera; those of the sacral division supply the vasculature of the large bowel, bladder, and genitalia. Resistance vessels are not thought to receive parasympathetic innervation, and the effect of the parasympathetic system on total resistance is minor. The parasympathetic system generally produces effects opposite those of the sympathetic division, i.e., decreased cardiac rate and output and vascular relaxation, but is thought to be of secondary importance in peripheral vascular regulation.
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