Reperfusion after acute coronary occlusion in dogs impairs endothelium-dependent relaxation to acetylcholine and augments contractile reactivity in vitro.

Abstract

Endothelial injury may contribute to the augmented coronary vascular tone seen in myocardial ischemia by impairing endothelial production or release of vasodilators. In vitro reactivity of arterial rings was studied after 60 min of coronary occlusion and 60 min of reperfusion in anesthetized dogs. Ischemia without reperfusion blunted contractile reactivity to potassium chloride (KCI), whereas ischemia plus reperfusion augmented contractile responses to both KCI and ergonovine. The response to acetylcholine, an endothelium-dependent vasodilator, was abolished in reperfused arteries, whereas the response to nitroprusside, an endothelium-independent vasodilator, was intact. Verapamil pretreatment restored KCI contractile responses to normal in reperfused coronary rings and partially restored endotheliumdependent relaxation. Electron microscopy revealed a nondenuding epicardial coronary endothelial injury in reperfused arteries. These data support the hypothesis that reperfusion of ischemic myocardium augments reactivity to vasoconstrictor agents by causing endothelial cell damage, excessive calcium influx, and loss of modulating vasodilator function. IntroductionCoronary artery "spasm" has been identified as the basis of "variant" or "Prinzmetal" angina (1, 2), as a precipitant ofmyocardial infarction (3), and as a frequent factor in unstable and postinfarction angina (4-6). The mechanism by which this abnormal form of coronary vasoconstriction occurs is not known. However, recent interest has focused on the vascular endothelium as a determinant of vasodilator tone. Furchgott described a chemical "relaxing" factor, which is produced by endothelial cells and vasodilates coronary and other systemic arteries (7). Damage to the endothelium may impair release of this relaxing factor or other endothelial-derived vasodilators, and cause vasoconstriction. Recent studies have assessed the role of the endothelium in modulating coronary vascular tone by mechanically removing the endothelium oflarge, epicardial coronary artenes. Deendothelialization produces spontaneous local vasoconstric-

Impaired endothelium‐dependent relaxation of dog coronary arteries after myocardial ischaemia and reperfusion: prevention by amlodipine, propranolol and allopurinol

“…These experiments confirmed previous findings (Ku, 1982;VanBenthuysen et al, 1987;Sobey et al, 1990a) that endotheliumdependent but not endothelium-independent vasorelaxation is impaired in vitro following an acute period of coronary ischaemia and reperfusion. We now show that three apparently unrelated pharmacological agents which are known to inhibit ischaemia-induced cardiac damage, amlodipine (a calcium antagonist), propranolol (a fi-adrenoceptor antagonist) and allopurinol (a xanthine oxidase inhibitor), all offer significant protection against the impairment of endothelium-dependent vasorelaxation by ischaemia and reperfusion.…”

“…Regional myocardial infarction and reduced cardiac function caused by an acute period of coronary artery occlusion and reperfusion is accompanied by vascular endothelial cell injury (Armiger & Gavin, 1975;Sobey et al, 1990a), large coronary artery constriction (Sobey et al, 1990a) and an impairment of endothelium-dependent coronary vasodilatation both in vivo and in vitro (Ku, 1982;VanBenthuysen et al, 1987;Mehta et al, 1989a,b;Sobey et al, 1990a).…”

Increased nitric oxide synthase activity despite lack of response to endothelium-dependent vasodilators in postischemic acute renal failure in rats.

“…Recent studies have demonstrated that ischemic or hypoxic injury to vital organs, including brain, lung, heart, and kidney, not only damages parenchymal cells but also affects the function and reactivity of the vasculature serving these organs (1)(2)(3)(4)(5)(6)(7). A general feature of the altered vasoreactivity is an augmented sensitivity to vasoconstrictor stimuli which, in turn, increases the vulnerability of the affected organ to additional ischemic attacks.…”

“…A general feature of the altered vasoreactivity is an augmented sensitivity to vasoconstrictor stimuli which, in turn, increases the vulnerability of the affected organ to additional ischemic attacks. Prinzmetal's and postinfarction angina, accelerating transient cerebral ischemic attacks, vasoconstriction after limb ischemia, and prolonged acute renal failure, at least in part, are thought to be clinical examples of postischemic hypersensitivity of the resistance vasculature (1)(2)(3)(4)(5)(6)(7)(8).…”

Myocardial ischemia results in tetrahydrobiopterin (BH 4 ) oxidation with impaired endothelial function ameliorated by BH 4

“…It was also observed previously that eNOS function is impaired in ischemic hearts (10). In vivo coronary artery occlusion triggers endothelial dysfunction and decreased eNOSdependent vasoreactivity, although reactivity is preserved to exogenous NO (11,12). Endothelial-dependent coronary vasoreactivity is impaired in hearts subjected to periods of global ischemia and reperfusion (10).…”