Increased myocardial oxygen consumption by TNF-alpha is mediated by a sphingosine signaling pathway.
The present study investigated the effect of tumor necrosis factor (TNF)-alpha on myocardial energy metabolism as estimated by myocardial oxygen consumption (MVo(2)). MVo(2) of electrically stimulated isolated trabeculae of right ventricular Wistar rat myocardium was analyzed using a Clark-type oxygen probe. After the initial data collection in the absence of TNF-alpha, measurements were repeated after TNF-alpha stimulation. In separate experiments, pretreatment with the nitric oxide (NO) synthase inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME) or the ceramidase inhibitor n-oleoylethanolamine (NOE) was done to investigate NO/sphingosine-related effects. TNF-alpha impaired myocardial economy at increasing stimulation frequencies without altering baseline MVo(2). Incubation with TNF-alpha in the presence of l-NAME further impaired myocardial economy. NOE preincubation abrogated the TNF-alpha effect on myocardial economy. Moreover, the negative inotropic effect of TNF-alpha was observed in NOE-pretreated but not l-NAME-pretreated muscle fibers. Exogenous sphingosine mimicked the TNF-alpha effect on mechanics and energetics. We conclude that TNF-alpha impairs the economy of chemomechanical energy transduction primarily through a sphingosine-mediated pathway.
Hofmann
Ulrich
U
Department of Medicine/Cardiology, University of Würzburg, Germany.
Domeier
Erik
E
Frantz
Stefan
S
Laser
Martin
M
Weckler
Barbara
B
Kuhlencordt
Peter
P
Heuer
Stefan
S
Keweloh
Boris
B
Ertl
Georg
G
Bonz
Andreas W
AW
D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D000818:Animals; D002118:Calcium / Q000378:metabolism; D055572:Ceramidases; D063388:Endocannabinoids; D004734:Energy Metabolism / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004983:Ethanolamines / Q000494:pharmacology; D066298:In Vitro Techniques; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000201:enzymology; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III; D009829:Oleic Acids; D010101:Oxygen Consumption / Q000502:physiology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013110:Sphingosine / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D004983:Ethanolamines; D009829:Oleic Acids; D014409:Tumor Necrosis Factor-alpha; C033595:N-oleoylethanolamine; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D000581:Amidohydrolases; D055572:Ceramidases; D013110:Sphingosine; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester