Circulation Research. 2002;90:807-813
Published online before print March 7, 2002, doi: 10.1161/01.RES.0000014451.75415.36
Published online before print March 7, 2002, doi: 10.1161/01.RES.0000014451.75415.36
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© 2002 American Heart Association, Inc.
Integrative Physiology |
Myocardial Dysfunction With Coronary Microembolization
Signal Transduction Through a Sequence of Nitric Oxide, Tumor Necrosis Factor-
, and Sphingosine
From Abteilung für Pathophysiologie, Zentrum für Innere Medizin, Universitätsklinikum Essen.
Correspondence to Prof Dr med Dr hc G. Heusch, Abteilung für Pathophysiologie, Zentrum für Innere Medizin, Universitätsklinikum Essen, Hufelandstraße 55, 45122 Essen, Germany. E-mail gerd.heusch{at}uni-essen.de
Coronary microembolization results in progressive myocardial dysfunction, with causal involvement of tumor necrosis factor-
(TNF-). TNF- 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-, 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 NG-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-µm diameter) per milliliter inflow into the left circumflex coronary artery. Posterior systolic wall thickening (PWT) remained unchanged in group 1 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-, and sphingosine contents were increased in the microembolized posterior myocardium. In group 3, PWT remained unchanged (20.3±2.6% at baseline) with intracoronary administration of L-NAME (20.8±3.4%) and 17.7±2.3% at 8 hours after microembolization; TNF- 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-, 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-, and sphingosine is causally involved in the coronary microembolization-induced progressive contractile dysfunction.
Key Words: coronary microembolization • tumor necrosis factor- • nitric oxide • sphingosine
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