Vesnarinone and amrinone reduce the systemic inflammatory response syndrome.

Abstract

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 beta 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 inflammatory signaling within certain tissues.

• Authors: K Takeuchi, P J del Nido, A E Ibrahim, H Cao-Danh, I Friehs, P Glynn, D Poutias, D B Cowan, F X McGowan Jr
• Journal: The Journal of thoracic and cardiovascular surgery (J Thorac Cardiovasc Surg) Vol. 117 Issue 2 Pg. 375-82 (Feb 1999) ISSN: 0022-5223 [Print] United States
• PMID: 9918980 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Adjuvants, Immunologic
• Endotoxins
• Inflammation Mediators
• Interleukin-1
• Phosphodiesterase Inhibitors
• Pyrazines
• Quinolines
• Tumor Necrosis Factor-alpha
• vesnarinone
• Nitric Oxide Synthase
• Nitric Oxide Synthase Type II
• Amrinone

Topics

• Adjuvants, Immunologic (therapeutic use)
• Amrinone (therapeutic use)
• Animals
• Drug Evaluation, Preclinical
• Endotoxemia (blood, chemically induced, drug therapy)
• Endotoxins
• Heart (drug effects, physiopathology)
• Inflammation Mediators (blood)
• Interleukin-1 (blood)
• Lung (drug effects, enzymology)
• Myocardium (enzymology)
• Nitric Oxide Synthase (drug effects, metabolism)
• Nitric Oxide Synthase Type II
• Phosphodiesterase Inhibitors (therapeutic use)
• Pyrazines
• Quinolines (therapeutic use)
• Rabbits
• Salmonella typhimurium
• Systemic Inflammatory Response Syndrome (blood, chemically induced, drug therapy)
• Time Factors
• Tumor Necrosis Factor-alpha (analysis)