SELECTIVE MODULATION OF INDUCIBLE NITRIC-OXIDE SYNTHASE ISOZYME IN MYOCARDIAL-INFARCTION

Background Inducible nitric oxide synthase (iNOS) is activated in card iac disorders, We investigated the contribution of increased iNOS acti vity to the development of left ventricular dysfunction after myocardi al infarction by selective inhibition of the isozyme. Methods and Resu lts Male New Zealand rabbits were subjected to myocardial infarction, Animals were treated with either saline, S-methylisothiourea sulfate ( SMT) (a selective iNOS inhibitor), or N-omega-nitro-L-arginine (L-NNA) (a nonselective NOS inhibitor). Inducible and constitutive NOS (cNOS) activity, plasma NOx, cGMP, hemodynamics, and myocardial blood flow w ere measured before and 5: 24, and 72 hours after coronary occlusion. Infarction 72 hours after occlusion resulted In increased myocardial i NOS activity, increased cardiac NOx production, and elevated cGMP leve ls. cNOS remained unchanged. Infarction increased left ventricular end -diastolic pressure (LVEDP) and decreased maximum +dP/dt and -dP/dt. L -NNA inhibited iNOS and cNOS activities and plasma NOx levels. L-NNA f urther increased LVEDP and reduced myocardial blood flow. Administrati on of SMT 72, hours after infarction significantly inhibited iNOS and cardiac NOx production but had no effects on cNOS. SMT improved left v entricular maximum +dP/dt and -dP/dt and decreased LVEDP. Myocardial b lood flow in the remote myocardium increased. Conclusions These findin gs suggest that induction of iNOS activity 72 hours after infarction e xerts negative inotropic effects and contributes to the development of myocardial dysfunction! selective modulation of increased iNOS activi ty by SMT improves cardiac performance, enhances myocardial blood flow , and may be beneficial in the treatment of acute myocardial infarctio n.