ROLE OF IMPAIRED ENDOTHELIUM-DEPENDENT VASODILATION IN ISCHEMIC MANIFESTATIONS OF CORONARY-ARTERY DISEASE

Abnormal constriction of the epicardial coronary arteries contributes to the pathogenesis of myocardial ischemia, not only in variant angina but also in patients with stable and unstable forms of angina. This a ugmented vasoconstrictor responsiveness associated with atherosclerosi s can in large part be attributed to an impairment in endothelium-depe ndent relaxation. When the endothelium is removed experimentally or is dysfunctional (as in atherosclerosis), normal vasodilation is replace d by paradoxical vasoconstriction. Infusion of acetylcholine into norm al coronary arteries of humans results in vasodilation, which is media ted by endothelium-derived relaxing factor (EDRF), presumably nitric o xide or a closely related substance. When acetylcholine is infused int o coronary arteries of patients with atherosclerosis, loss of dilation and paradoxical constriction are observed. This abnormal coronary res ponse to acetylcholine reflects impairment of EDRF due to either its d iminished release and/or increased inactivation. Similar reductions in endothelium-dependent coronary dilation in patients with atherosclero sis have been observed in response to other pharmacological or physiol ogical stimuli-serotonin, blood flow, and catecholamines-and to a less er degree in response to substance P. Normal human epicardial coronary arteries dilate during daily activities such as exercise, mental stre ss, or exposure to cold. This dilation is mediated by increases in blo od flow (and thereby EDRF) in response to increasing metabolic demand. In healthy vessels, this dilation overcomes the constrictor influence s of catecholamines (predominantly norepinephrine) that are released l ocally from nerve endings during these activities. Atherosclerosis, by impairing EDRF, leaves the vasoconstrictor influence of catecholamine s unopposed. The resultant abnormal coronary constriction, when superi mposed on stenoses, is likely to be an important contributing mechanis m of myocardial ischemia by further reducing the available coronary bl ood flow reserve. The setting of exertion-related coronary constrictio n is of greatest importance among patients with stable angina. Episode s of unstable angina may occur at rest, unrelated to physical exertion . The pathological findings in this condition include the presence of a complex, degenerated plaque; intracoronary platelet aggregates; and thrombus. Serotonin, a product released from aggregating platelets, an d thrombin, formed by the coagulation cascade, have been shown to dila te normal coronary arteries by the release of EDRF. Atherosclerotic ar teries, which are deficient in EDRF, are paradoxically constricted by serotonin and thrombin. Thus, although the underlying culprit in the p athogenesis of abnormal coronary vasoconstriction is an impairment of endothelium-dependent dilation, the specific triggering mechanisms tha t lead to the unopposed vasoconstriction may differ in various forms o f angina. Abnormal responses to catecholamines and blood How are more germane in patients with stable angina, whereas responses to serotonin and possibly to thrombin are more relevant to patients with unstable forms of angina. Recent experimental and clinical studies have suggest ed that the abnormalities of endothelium-dependent relaxation in ather osclerosis may extend to the microvasculature even though these vessel s are free of overt pathology. In patients with nonobstructive coronar y atherosclerosis, the flow responses of small vessels to acetylcholin e, substance P, and rapid pacing have been shown to be markedly blunte d. These findings may have profound implications regarding the ability of atherosclerotic arteries to regulate their blood flow, as the smal l vessels are where metabolic regulation normally resides.