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Pedro J. del Nido
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J Thorac Cardiovasc Surg 1999;117:375-382
© 1999 Mosby, Inc.

CARDIOPULMONARY SUPPORT AND PHYSIOLOGY

VESNARINONE AND AMRINONE REDUCE THE SYSTEMIC INFLAMMATORY RESPONSE SYNDROME

Koh Takeuchi, MD, Pedro J. del Nido, MD, Andra E. Ibrahim, MD, Hung Cao-Danh, PhD, Ingeborg Friehs, MD, Paul Glynn, PhD, Dimitrios Poutias, BS, Douglas B. Cowan, PhD, Francis X. McGowan, Jr, MD

From the Department of Cardiac Surgery and the Anesthesiology/ Critical Care Medicine Laboratory, Children's Hospital and Harvard Medical School, Boston, Mass.

Supported in part by National Institutes of Health grants HL-52589 (F.X.M.) and HL46207 (P.J.D.).

Read at the Seventy-eighth Annual Meeting of The American Association for Thoracic Surgery, Boston, Mass, May 3-6, 1998.

Received for publication May 8, 1998. Revisions requested July 7, 1998. Revisions received Aug 20, 1998. Accepted for publication Sept 14, 1998. Address for reprints: Francis X. McGowan, Jr, MD, Cardiac Anesthesia Service, Children's Hospital, 300 Longwood Ave, Boston, MA 02115.

Objective: The systemic inflammatory response is an important cause of organ dysfunction. The present study tested the hypothesis that 2 clinically used agents, amrinone and vesnarinone, would decrease inflammation and cardiac dysfunction in a relevant model of systemic inflammatory response activation.
Methods: Rabbits received intravenous endotoxin, alone or in conjunction with amrinone or vesnarinone. Systemic effects were assessed by death, fever, behavior, and acidosis. Measures of inflammatory signaling were (1) plasma tumor necrosis factor-{alpha} and interleukin-1 ß production, (2) lung tissue myeloperoxidase activity, and (3) myocardial inducible nitric oxide synthase activity. Indices of systolic and diastolic myocardial function were measured in Langendorff-perfused hearts.
Results: Vesnarinone, in particular, reduced mortality rates (19% vs 61% for lipopolysaccharide alone, P = .01) and acidosis in lipopolysaccharide-treated rabbits. Both agents markedly reduced systemic tumor necrosis factor and interleukin-1 concentrations, lipopolysaccharide-mediated effects on myocardial systolic and diastolic function and on myocardial inducible nitric oxide synthase activity. Vesnarinone, but not amrinone, (1) decreased fever and lethargy, consistent with decreased central nervous system effects of endotoxin, and (2) decreased lung leukocyte infiltration.
Conclusions: Vesnarinone and amrinone, which are used clinically for their inotropic and vasodilating properties, may be useful to limit inflammatory activation and consequent organ dysfunction. Structure-activity and/or pharmacokinetic between the compounds may be important, particularly in preventing inflamatory signaling within certain tissues.




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