Reduction of myocardial infarct size by inhibition of inducible nitric oxide synthase

Abstract

The inducible nitric oxide synthase isoform (iNOS) is upregulated by cytokines and endotoxins in many types of cells, including cardiac myocytes. Nitric oxide (NO) induced by cytokines can be cytotoxic, and has been implicated in the pathophysiology of myocardial infarction, cardiomyopathy, and septic shock. To examine the role of iNOS in the ischemic myocardium, we studied: 1) the time course of expression of iNOS mRNA after myocardial infarction (MI) in male Sprague-Dawley rat hearts and expression of iNOS protein in the infarcted region; 2) whether hypoxia in vitro is a potential mediator of the induction of iNOS mRNA; and 3) whether inhibition of iNOS by two different selective inhibitors (aminoguanidine and S-methylisothiourea sulfate) in vivo influences infarct size. Myocardial infarction was induced by ligation of the left anterior descending coronary artery (LAD), and tissue was collected at selected times thereafter from both ligated and sham-operated rats. iNOS mRNA was induced in the infarcted region of the left ventricle for 7 days; iNOS protein was also detected in the infarcted area. We next tested whether hypoxia would induce iNOS in vitro. In cultured neonatal ventricular myocytes, iNOS mRNA was slightly induced by 6 to 24 h of hypoxia; however, iNOS protein was only detected when the cytokine interleukin-1β was present. To study whether iNOS activity contributed to myocardial damage (eg, infarct size), we administered the first dose of the NOS inhibitors 24 h before LAD occlusion and then a second dose after surgery. Inhibition of iNOS activity with aminoguanidine reduced infarct size by 20% but had no effect on infiltration by neutrophils, whereas the more selective inhibitor S-methylisothiourea sulfate reduced infarct size by 41%. These data suggest that NO derived from the iNOS isoform contributes to some of the myocardial injury following MI, possibly by causing myocardial cell death in areas bordering the ischemic region of the heart.