The role of the L-arginine/nitric oxide pathway in myocardial ischaemic and reperfusion injury.
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.
Pernow
J
J
Department of Cardiology, Karolinska Hospital, Stockholm, Sweden.
Wang
Q D
QD
D000818:Animals; D001120:Arginine / Q000378:metabolism* / Q000627:therapeutic use; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology; D003402:Creatine Kinase / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D009203:Myocardial Infarction / Q000473:pathology; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D019335:Nitroarginine / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000627:therapeutic use; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine
D004791:Enzyme Inhibitors; C110881:S-nitro-N-acetylpenicillamine; D019335:Nitroarginine; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D003402:Creatine Kinase; D010396:Penicillamine