Influence of peroxynitrite on energy metabolism and cardiac function in a rat ischemia-reperfusion model.
Ischemia-reperfusion generates peroxynitrite (ONOO-), which interacts with many of the systems altered by ischemia-reperfusion. This study examines the influence of endogenously produced ONOO- on cardiac metabolism and function. Nitro-L-arginine (an inhibitor of ONOO- biosynthesis) and urate (a scavenger of ONOO-) were utilized to investigate potential pathophysiological roles for ONOO- in a rat Langendorff heart model perfused with glucose-containing saline at constant pressure and exposed to 30 min of ischemia followed by 60 min of reperfusion. In this model, ischemia-reperfusion decreased contractile function (e.g., left ventricular developed pressure), cardiac work (rate-pressure product), efficiency of O2 utilization, membrane-bound creatine kinase activity, and NMR-detectable ATP and creatine phosphate without significantly altering the recovery of coronary flow, heart rate, lactate release, and muscle pH. Treatment with urate and nitro-L-arginine produced a substantial recovery of left ventricular developed pressure, rate-pressure product, efficiency of O2 utilization, creatine kinase activity, and NMR-detectable creatine phosphate and a partial recovery of ATP. The pattern of effects observed in this study and in previously published work with similar models suggests that ONOO- may alter key steps in the efficiency of mitochondrial high-energy phosphate generation.
Lee
Warren H
WH
Metabolic Cardiovascular Diseases, Novartis Institute for Biomendical Research, Summit, New Jersey 07901, USA.
Gounarides
John S
JS
Roos
Eric S
ES
Wolin
Michael S
MS
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D002462:Cell Membrane / Q000201:enzymology; D003402:Creatine Kinase / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D066298:In Vitro Techniques; D043322:Lactase; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D010101:Oxygen Consumption; D030421:Peroxynitrous Acid / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology*; D013482:Superoxide Dismutase / Q000494:pharmacology; D014527:Uric Acid / Q000494:pharmacology; D001616:beta-Galactosidase / Q000378:metabolism
D002316:Cardiotonic Agents; D030421:Peroxynitrous Acid; D019335:Nitroarginine; D014527:Uric Acid; D009569:Nitric Oxide; D013482:Superoxide Dismutase; D003402:Creatine Kinase; D043322:Lactase; D001616:beta-Galactosidase