Prevention of early myocardial depression in hyperdynamic endotoxemia in dogs

In our study the pathomechanism of sepsis-induced early myocardial depressi on was investigated. We determined the effects of the inducible nitric oxid e synthase inhibitor and free radical scavenger mercaptoethylguanidine (MEG ) on the myocardial contractility, the endothelial and inducible nitric oxi de synthase (eNOS and iNOS) activities, and the activation and tissue accum ulation of polymorphonuclear leukocytes in hyperdynamic endotoxemia in dogs . Group 1 served as endotoxemic control. Mean arterial pressure and cardiac output were measured, myocardial contractility was estimated from the end- systolic pressure-diameter relationship. The eNOS, iNOS and myeloperoxidase activities were determined on myocardial biopsy samples, and the free radi cal-producing capacity of granulocytes was measured from separated cells. T he effect of MEG on the in vitro free radical production of isolated granul ocytes was measured by chemiluminometry. Endotoxin induced a hyperdynamic c irculatory reaction and significant myocardial depression. The myocardial e NOS activity was significantly increased 4 h after induction of endotoxemia and remained elevated, the iNOS activity was increased only 8 h after endo toxemia induction. The free radical-producing capacity and the myocardial a ccumulation of the granulocytes were significantly increased, In group 2, M EG treatment selectively inhibited the iNOS activity, prolonged the hyperdy namic circulatory reaction, prevented myocardial depression and decreased t he activation and tissue accumulation of granulocytes, The compound dose-de pendently decreased the in vitro activation of previously resting granulocy tes. Our study demonstrates that iNOS do not contribute to the early cardia c failure in endotoxemia. MEG selectively inhibits iNOS in vivo, but its be neficial effects are rather related to the decreases in leukocyte and free radical-mediated myocardial dysfunction during early endotoxemia.