Protonic inhibition of the mitochondrial oligomycin-sensitive adenosine 5'-triphosphatase in ischemic and autolyzing cardiac muscle. Possible mechanism for the mitigation of ATP hydrolysis under nonenergizing conditions.
Ischemic myocardium was produced by occluding the left circumflex coronary artery in anesthetized dogs for 10 or 20 min. Autolyzed myocardium was produced by incubating transmural samples of canine left ventricle at 37 degrees C for 5, 10, 15, 20, 40, or 60 min. Tissue pH was recorded continuously in each model using a microcombination pH electrode impaled into the midmyocardium. Mitochondria isolated from both ischemic and autolyzed tissue exhibited marked parallel depressions of oligomycin-sensitive ATPase activity, Km ATP, and Vmax. All of these parameters dropped more markedly during the zero flow autolytic process than during the low flow ischemia characteristic of the canine left circumflex occlusion model. The changes in the ATPase kinetic parameters paralleled closely the drop in tissue pH in each model. These ATPase kinetic changes were then reproduced in vitro both quantitatively and qualitatively by incubating isolated control mitochondria at the same pH values under nonenergizing conditions. It thus became evident that we had, in effect, utilized the oligomycin-sensitive ATPase as an in situ indicator of cell acidosis. Reperfusion of 15-min ischemic myocardium was accompanied by a complete reversal of the acidosis and of the ATPase activity inhibition. The ATPase inhibition demonstrable in vitro in isolated mitochondria occurred when the pH was lowered, but only when there was a concomitant dissipation of the transmembrane electrochemical gradient. The ATPase inhibition was then reversed completely during a subsequent state 4 incubation by a carbonyl cyanide p-trifluoromethoxyphenylhydrazone-sensitive process.
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D003327:Coronary Disease / Q000201:enzymology*; D004285:Dogs; D005260:Female; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D008297:Male; D008929:Mitochondria, Heart / Q000201:enzymology*; D009840:Oligomycins / Q000494:pharmacology*
D009840:Oligomycins; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases