The role of the L-arginine/nitric oxide pathway in myocardial ischaemic and reperfusion injury.

Abstract

Myocardial ischaemia followed by reperfusion (I/R) is associated with impaired endothelial function including diminished release and/or effects of nitric oxide (NO) which may contribute to the development of I/R injury. The aim of the present study was to investigate the role of the L-arginine/NO pathway in myocardial I/R injury. In isolated rat hearts subjected to global ischaemia followed by reperfusion L-arginine and the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP), but not D-arginine, significantly enhanced the recoveries of mycardial performance and coronary flow, and reduced the area of no-reflow and creatine kinase outflow. The NO synthase inhibitor NG-nitro-L-arginine (L-NNA) abolished the protective effects of L-arginine. Endothelium-dependent vasodilatation after I/R was preserved in L-arginine treated but not in vehicle hearts. Following I/R Ca2+-dependent NO synthase activity was reduced by 90% in comparison with non-ischaemic hearts. L-arginine but not D-arginine significantly increased NO synthase activity. In anaesthetized pigs, L-arginine given by local coronary venous retroinfusion reduced myocardial infarct size induced by 45 min of coronary artery ligation and 4 h of reperfusion to 35% of the area at risk from 76% in controls. The protective effect of L-arginine was blocked by L-NNA. Acetylcholine-induced coronary vasodilatation following I/R was attenuated in controls but not in L-arginine treated pigs. It is concluded that L-arginine or the NO donor SNAP reduces I/R-induced myocardial and endothelial injury. The protective effect of L-arginine seems to be mediated through maintained production of NO by preserving the function of Ca2+-dependent NO synthase in the heart.