Increased Inducible Nitric Oxide Synthase Expression Contributes to Myocardial Dysfunction and Higher Mortality After Myocardial Infarction in Mice

Background—Inducible nitric oxide synthase (iNOS) is expressed in the myocardium after myocardial infarction (MI) and in heart failure. Its pathophysiological role in these conditions, however, is not clear. We hypothesized that increased NO production from iNOS expression causes myocardial dysfunction and results in higher mortality after MI. Methods and Results—MI was induced by left coronary artery ligation in iNOS2/2 mutant and wild-type mice. Mortality was followed up for 30 days. MI resulted in a significant increase in mortality in both iNOS2/2 and wild-type mice compared with sham operation (P,0.01). Mortality was significantly decreased and LV myocardial contractility was increased, however, in iNOS2/2 mice compared with the wild-type mice (P,0.05). Five days after MI, myocardial iNOS mRNA expression, plasma nitrate and nitrite concentrations, and myocardial and plasma nitrotyrosine levels were significantly increased in wild-type compared with iNOS2/2 mutant mice (P,0.05). Both basal LV 1dP/dt and its response to dobutamine were significantly increased in iNOS2/2 compared with the wild-type mice (P,0.05). Conclusions—Increased NO production from iNOS expression contributes to myocardial dysfunction and mortality after MI in mice. (Circulation. 2001;104:700-704.) Key Words: heart failure n nitric oxide n nitric oxide synthase n myocardial infarction Nitric oxide (NO) is produced from L-arginine by a familyof NO synthases. Three distinct isoforms of nitric oxide synthase (NOS), derived from separate genes, are neural NO