title: Myocardial dysfunction with coronary microembolization: signal transduction through a sequence of nitric oxide, tumor necrosis factor-alpha, and sphingosine.
abstract: Coronary microembolization results in progressive myocardial dysfunction, with causal involvement of tumor necrosis factor-alpha (TNF-alpha). TNF-alpha 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-alpha, 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-microm 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-alpha, 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-alpha 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-alpha, and sphingosine is causally involved in the coronary microembolization-induced progressive contractile dysfunction.
authors.affiliation: Abteilung für Pathophysiologie, Zentrum für Innere Medizin, Universitätsklinikum Essen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Thielmann
authors.forename: Hilmar
authors.initials: H
authors.lastname: Dörge
authors.forename: Claus
authors.initials: C
authors.lastname: Martin
authors.forename: Sergej
authors.initials: S
authors.lastname: Belosjorow
authors.forename: Uwe
authors.initials: U
authors.lastname: Schwanke
authors.forename: Anita
authors.initials: A
authors.lastname: van De Sand
authors.forename: Ina
authors.initials: I
authors.lastname: Konietzka
authors.forename: Astrid
authors.initials: A
authors.lastname: Büchert
authors.forename: Arne
authors.initials: A
authors.lastname: Krüger
authors.forename: Rainer
authors.initials: R
authors.lastname: Schulz
authors.forename: Gerd
authors.initials: G
authors.lastname: Heusch
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001783:Blood Flow Velocity; D055572:Ceramidases; D003326:Coronary Circulation; D003327:Coronary Disease / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004285:Dogs; D004617:Embolism / Q000150:complications / Q000503:physiopathology*; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004983:Ethanolamines / Q000494:pharmacology; D007958:Leukocyte Count; D008863:Microspheres; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009829:Oleic Acids; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D004983:Ethanolamines; D009829:Oleic Acids; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C033595:N-oleoylethanolamine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D000581:Amidohydrolases; D055572:Ceramidases; D013110:Sphingosine; D019331:NG-Nitroarginine Methyl Ester