Prevention of early myocardial depression in hyperdynamic endotoxemia in dogs.
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.
Wolfárd
A
A
Institute of Experimental Surgery, Szent-Györgyi Albert Medical University, Szeged, Hungary.
Kaszaki
J
J
Szabó
C
C
Szalay
L
L
Nagy
S
S
Boros
M
M
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D004285:Dogs; D019446:Endotoxemia / Q000503:physiopathology*; D004731:Endotoxins; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004926:Escherichia coli; D016166:Free Radical Scavengers / Q000494:pharmacology; D006146:Guanidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D018805:Sepsis / Q000503:physiopathology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D004731:Endotoxins; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D006146:Guanidines; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D013755:Tetradecanoylphorbol Acetate; C100078:2-mercaptoethylguanidine