Vesnarinone and amrinone reduce the systemic inflammatory response syndrome

Objective: The systemic inflammatory response is an important cause of orga n dysfunction, The present study tested the hypothesis that 2 clinically us ed agents, amrinone and vesnarinone, would decrease inflammation and cardia c dysfunction in a relevant model of systemic inflammatory response activat ion. Methods: Rabbits received intravenous endotoxin, alone or in conjuncti on with amrinone or vesnarinone. Systemic effects were assessed by death, f ever, behavior, and acidosis. Measures of inflammatory signaling were (1) p lasma tumor necrosis factor-cc and interleukin-1 beta production, (2) lung tissue myeloperoxidase activity, and (3) myocardial inducible nitric oxide synthase activity. Indices of systolic and diastolic myocardial function we re measured in Langendorff-perfused hearts. Results: Vesnarinone, in partic ular, reduced mortality rates (19% vs 61% for lipopolysaccharide alone, P = .01) and acidosis in lipopolysaccharide-treated rabbits. Both agents marked ly reduced systemic tumor necrosis factor and interleukin-l concentrations, lipopolysaccharide-mediated effects on myocardial systolic and diastolic f unction and on myocardial inducible nitric oxide synthase activity. Vesnari none, but not amrinone, (1) decreased fever and lethargy, consistent with d ecreased central nervous system effects of endotoxin, and (2) decreased lun g leukocyte infiltration, Conclusions: Vesnarinone and amrinone, which are used clinically for their inotropic and vasodilating properties, may be use ful to limit inflammatory activation and consequent organ dysfunction, Stru cture-activity and/or pharmacokinetic between the compounds may be importan t, particularly in preventing inflamatory signaling within certain tissues.