In our study the pathomechanism of
sepsis-induced early myocardial depression was investigated. We determined the effects of the
inducible nitric oxide synthase inhibitor and
free radical scavenger mercaptoethylguanidine (MEG) on the myocardial contractility, the endothelial and
inducible nitric oxide synthase (eNOS and iNOS) activities, and the activation and tissue accumulation 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 radical-producing capacity of granulocytes was measured from separated cells. The effect of MEG on the in vitro
free radical production of isolated granulocytes was measured by chemiluminometry.
Endotoxin induced a hyperdynamic circulatory reaction and significant myocardial depression. The myocardial eNOS activity was significantly increased 4 h after induction of
endotoxemia and remained elevated, the iNOS activity was increased only 8 h after
endotoxemia induction. The
free radical-producing capacity and the myocardial accumulation of the granulocytes were significantly increased. In group 2, MEG treatment selectively inhibited the iNOS activity, prolonged the hyperdynamic circulatory reaction, prevented myocardial depression and decreased the activation and tissue accumulation of granulocytes. The compound dose-dependently decreased the in vitro activation of previously resting granulocytes. Our study demonstrates that iNOS do not contribute to the early
cardiac failure in
endotoxemia. MEG selectively inhibits iNOS in vivo, but its beneficial effects are rather related to the decreases in leukocyte and
free radical-mediated myocardial dysfunction during early
endotoxemia.