Intra-coronary administration of L-arginine aggravates myocardial stunning through production of peroxynitrite in dogs.

Abstract

The aim of this study was to investigate how the enhanced nitric oxide (NO) production by intra-coronary infusion of L-arginine acts in myocardial stunning in dogs by focusing on the involvement of peroxynitrite, a reaction product of NO and superoxide anion. Dogs were divided into six groups; a control non-treated group (CON, n = 9), and NG-nitro L-arginine methyl ester (L-NAME, n = 6), 1 mM L-arginine (L-ARG, n = 8), D-arginine (D-ARG, n = 6), L-arginine plus superoxide dismutase (L-ARG + SOD, n = 6), and SOD alone (SOD, n = 6) treated groups. L-NAME, or L- or D-arginine was continuously infused into the left anterior descending coronary artery (LAD) starting just prior to reperfusion, whereas SOD was intravenously injected before occlusion. During 120 min of reperfusion after 15 min occlusion of LAD, myocardial contractile function in the ischemic region gradually recovered and reached approximately 70% of the preischemic level in CON, D-ARG and SOD, but it remained dyskinetic (-46%) in L-ARG. On the other hand, it was improved in L-NAME (90%). Tissue malondialdehyde was elevated (p < 0.005) after reperfusion, and myocardial NO metabolites measured by an intratissue-microdialyzer increased (approximately 150%, p < 0.05) in the ischemic region during reperfusion in L-ARG but not in the CON, L-NAME, D-ARG or SOD groups. In the L-ARG + SOD group, L-arginine-induced contractile dysfunction and elevation of malondialdehyde were prevented, but the increase in NO metabolites remained. These results suggest that L-arginine aggravated myocardial stunning through oxidative stress and the cytotoxicity was caused by NO derivatives but not by NO itself. The formation of nitrotyrosine, a footprint of peroxynitrite, was immunohistochemically confirmed in the ischemic region of L-ARG. Our results demonstrate for the first time in vivo that NO has a detrimental role in myocardial stunning through the production of peroxynitrite.