Proinflammatory cytokines depress cardiac efficiency by a nitric oxide-dependent mechanism.
Proinflammatory cytokines (interleukin-1beta, tumor necrosis factor-alpha, and interferon-gamma; Cytomix) depress myocardial contractile work partially by stimulating expression of inducible nitric oxide (NO) synthase (iNOS). Because NO and peroxynitrite inhibit myocardial O2 consumption (MVO2), we examined whether this mechanism contributes to reduced cardiac work. In control isolated working rat hearts, cardiac work was stable for 60 min, followed by a decline from 60 to 120 min, without change in MVO2. Cardiac efficiency (work/MVO2) was therefore reduced from 60 to 120 min. Cytomix shortened the onset (within 20-40 min) and enhanced the depression in cardiac work and efficiency and inhibited MVO2 after 80 min. Mercaptoethylguanidine (MEG), an iNOS inhibitor and peroxynitrite scavenger, or the glucocorticoid dexamethasone (Dex) abolished the effects of Cytomix. iNOS expression was increased 10-fold by Cytomix and abolished by Dex but not MEG. That cytokine-induced depression in cardiac work precedes the reduction in MVO2 suggests, at least in the early response, that NO and/or peroxynitrite may not impair heart function by inhibiting mitochondrial respiration but reduce the heart's ability to utilize ATP for contractile work.
Departments of Pediatrics and Pharmacology, Cardiovascular Research Group, University of Alberta, Edmonton, Alberta, Canada T6G 2S2.
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Panas
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Khadour
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Szabó
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Schulz
D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers; D006146:Guanidines / Q000494:pharmacology; D006329:Heart Conduction System / Q000187:drug effects; D007371:Interferon-gamma / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism; D009566:Nitrates / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D006146:Guanidines; D007375:Interleukin-1; D009566:Nitrates; D014409:Tumor Necrosis Factor-alpha; C039642:peroxynitric acid; D009569:Nitric Oxide; D003907:Dexamethasone; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C100078:2-mercaptoethylguanidine