Circulation Research. 2002
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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Submitted on October 19, 2001
Revised on January 17, 2002
Accepted on February 21, 2002
Myocardial Dysfunction With Coronary Microembolization. Signal Transduction Through a Sequence of Nitric Oxide, Tumor Necrosis Factor-
, and Sphingosine
Matthias Thielmann ;
From Abteilung für Pathophysiologie, Zentrum für Innere Medizin, Universitätsklinikum Essen.
* To whom correspondence should be addressed. 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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