Inducible nitric oxide synthase activation after ischemia/reperfusion contributes to myocardial dysfunction and extent of infarct size in rabbits: evidence for a late phase of nitric oxide-mediated reperfusion injury

Background: Ischemia/reperfusion (I/R) leads to the induction of inducible nitric oxide synthase. The present study investigated the effects of select ive and continuous inhibition of iNOS on myocardial performance, infarct si ze and histomorphological changes after I/R in rabbits. Methods and Results : Ischemia/reperfusion (I/R) was induced by occlusion of the circumflex cor onary artery for 30 min followed by 48 h of reperfusion. Sham animals (grou p A) served as control. Three groups were subjected to I/R: (B) placebo; (C ) aminoguanidine (AMG; 10 mg/kg bolus) given prior to and 48 h after I/R to test its acute effects; (D) AMG (300 mg/kg/day sc) to test effects of cont inuous treatment. Hemodynamics, myocardial blood flow, infarct size, iNOS a ctivity, cGMP levels, immunohistochemical analysis of iNOS expression and A MG tissue levels were determined. Continuous AMG treatment improved myocard ial performance (hemodynamics and blood flow) compared to placebo group. iN OS was highest in placebo-treated animals. AMG tissue levels were highest i n tissues affected by I/R. Infarct size (% of the circumflex region) was si gnificantly smaller in group B when compared to group B. Conclusions: This is the first study showing that activation of myocardial iNOS isozyme durin g 48 h of reperfusion contributes to a late phase of I/R-induced injury in rabbits. Selective and continuous modulation of iNOS by AMG over this time period exerts protective effects with respect to myocardial performance, co ronary blood flow, cellular infiltration and reduction of infarct size; thi s may be a novel therapeutic approach in the clinical situation to limit ir reversible myocardial injury associated with ischemia and reperfusion. (C) 1999 Elsevier Science B.V. All rights reserved.