Endothelin and nitric oxide in coronary vascular regulation with special reference to myocardial ischemia/reperfusion injury

Abstract: Endothelin and Nitric Oxide in Coronary Vascular Regulationwith special reference to myocardial ischemia/reperfusion injury Qing-Dong Wang Division of Cardiology, Department of Medicine and Division of Experimental Surgery, Department of Surgery, Karolinska Hospital, Stockholm, SwedenThe vascular endothelium plays an important role in the regulation of cardiovascular function byproducing bioactive substances such as nitric oxide (NO) and endothelin- I (ET- 1). Recent evidencehas revealed that endothelial dysfunction is closely related to myocardial ischemia/reperfusioninjury. The main purpose of the present study was to investigate the roles of ET- I and NO in theregulation of coronary circulation, particularly in the pathophysiology of myocardial ischemia/reperfusion injury.Exogenous ET-l caused profound coronary vasoconstriction in the pig in vivo and in vitro as wellas in the isolated rat heart. ET-I-induced vasoconstnction is mainly mediated by ETA receptoractivation. ETB receptor activation also evoked vasoconstriction in porcine coronary vasculature butelicited vasodilatation in the isolated rat heart via a mechanism related to release of NO.Reperfusion following coronary ligation or thrombosis resulted in a significant increase in thecoronary venous plasma level and myocardial overflow of ET-like immunoreactivity (-LI) in pigs,indicating a local release of ET from the affected myocardium. In the ischemic/reperfusedmyocardium the concentration of ET-LI was 3-7 fold higher than in the non-ischemic area suggestingenhanced synthesis of ET following ischemia/reperfusion. This increase in myocardial ET-LI wasattenuated by local coronary venous retroinfusion of L-arginine, but not by D-arginine, indicatingthat L-arginine inhibits ET synthesis via NO formation. Following ischemia/reperfusion thecoronary vasoconstrictor response to ET-I but not to an ETB receptor agonist was enhanced,suggesting that ischemia/reperfusion increases ihe vascular reactivity to ET- I through a mechanismrelated to ETA receptor activation. Moreover, this enhancement of vascular response to ET- I was notdue to a diminished release of NO or prostacyclin by the endothelium.Bosentan, a nonpeptide ETA and ETB receptor antagonist, reduced myocardial infarct size by 58%and 48% following ischemia/reperfusion in anesthetized pigs, when given intravenously and locallyas coronary venous retroinfusion, respectively. It also preserved the coronary flow during reperfusion.In the isolated rat heart bosentan and L-arginine improved the recovery of cardiac performance andpreserved endothelium-dependent vasorelaxation following ischemia/reperfusion. The effect of L-arginine was abolished by the NO synthase inhibitor L-NNA, but mimicked by an NO donor SNAP,suggesting that the cardioprotective effect of L-arginine acts through a mechanism related to NOformation. Myocardial ischemia/reperfusion reduced Ca2+-dependent NO synthase activity in theisolated rat heart and this effect was prevented by L-arginine.In conclusion, myocardial ischemia/reperfusion is associated with changes in synthesis, release andvascular actions of endothelial factors. The cardioprotective effects of the ET receptor antagonist andthe NO substrate L-arginine suggest that endogenous ET-1 and the L-arginine/NO pathway playimportant roles in the development of myocardial ischemia/reperfusion injury.Key words: endothelium, endothelin, myocardial ischemia, myocardial infarction, reperfusion, L-arginine, nitric oxide.