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

Abstract

The vascular endothelium plays an important role in the regulation of cardiovascular function by producing bioactive substances such as nitric oxide (NO) and endothelin-I (ET- 1). Recent evidence has revealed that endothelial dysfunction is closely related to myocardial ischemia/reperfusion injury.

The main purpose of the present study was to investigate the roles of ET- I and NO in the regulation 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 well as in the isolated rat heart. ET-I-induced vasoconstriction is mainly mediated by ETA receptor activation. ETB receptor activation also evoked vasoconstriction in porcine coronary vasculature but elicited 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 the coronary 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/reperfused myocardium the concentration of ET-LI was 3-7 fold higher than in the non-ischemic area suggesting enhanced synthesis of ET following ischemia/reperfusion. This increase in myocardial ET-LI was attenuated by local coronary venous retroinfusion of L-arginine, but not by D-arginine, indicating that L-arginine inhibits ET synthesis via NO formation. Following ischemia/reperfusion the coronary vasoconstrictor response to ET-I but not to an ETB receptor agonist was enhanced, suggesting that ischemia/reperfusion increases the vascular reactivity to ET- I through a mechanism related to ETA receptor activation. Moreover, this enhancement of vascular response to ET- I was not due 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 locally as 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 and preserved 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 NO formation. Myocardial ischemia/reperfusion reduced Ca2+-dependent NO synthase activity in the isolated rat heart and this effect was prevented by L-arginine.

In conclusion, myocardial ischemia/reperfusion is associated with changes in synthesis, release and vascular actions of endothelial factors. The cardioprotective effects of the ET receptor antagonist and the NO substrate L-arginine suggest that endogenous ET-1 and the L-arginine/NO pathway play important roles in the development of myocardial ischemia/reperfusion injury.