4.7 Article

Myocardial dysfunction with coronary microembolization -: Signal transduction through a sequence of nitric oxide, tumor necrosis factor-α, and sphingosine

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CIRCULATION RESEARCH
卷 90, 期 7, 页码 807-813

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LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.RES.0000014451.75415.36

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coronary microembolization; tumor necrosis factor-alpha; nitric oxide; sphingosine

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Coronary microembolization results in progressive myocardial dysfunction, with causal involvement of tumor necrosis factor-alpha (TNF-alpha). TNF-a uses a signal transduction involving nitric oxide (NO) and/or sphingosine. Therefore, we induced coronary microembolization in anesthetized dogs and studied the role and sequence of NO, TNF-a, and sphingosine for the evolving contractile dysfunction. Four sham-operated dogs served as controls (group 1). Eleven dogs received placebo (group 2), 6 dogs received the NO synthase inhibitor N-G-nitro-L-arginine methyl ester (L-NAME, group 3), and 6 dogs received the ceramidase inhibitor N-oleoylethanolamine (NOE, group 4) before microembolization was induced by infusion of 3000 microspheres (42-mum diameter) per milliliter inflow into the left circumflex coronary artery. Posterior systolic wall thickening (PWT) remained unchanged in group I but decreased progressively in group 2 from 20.6+/-4.9% (mean+/-SD) at baseline to 4.1+/-3.7% at 8 hours after microembolization. Leukocyte count, TNF-a, and sphingosine contents were increased in the microembolized posterior myocardium. In group 3, PWT remained unchanged (20.3+/-2.67% at baseline) with intracoronary administration of L-NAME (20.8+/-3.4%) and 17.7+/-2.3% at 8 hours after microembolization; TNF-a and sphingosine contents were not increased. In group 4, PWT also remained unchanged (20.7+/-4.6% at baseline) with intravenous administration of NOE (19.5+/-5.7%) and 16.4+/-6.3% at 8 hours after microembolization; TNF-alpha, but not sphingosine content, was increased. In all groups, systemic hemodynamics, anterior systolic wall thickening, and regional myocardial blood flow remained unchanged throughout the protocols. A signal transduction cascade of NO, TNF-a, and sphingosine is causally involved in the coronary microembolization-induced progressive contractile dysfunction.

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