Biphasic mitochondrial response after reversible ischemia is related to changes in calcium and glycolysis

t REVERSIBLE ISCHEMIA IS RELATED TO CHANGES IN CALCIUM AND GLYCOLYSIS Coert J Zuurbier* and Can Ince,Dept. of Anesthesiology and Physiology, Academic Medical Center, U. of Amsterdam, NL The response time of mitochondrial 02 consumption to changes in heart rate (tmito) in intact myocardium was examined as a function of duration of ischemia and reperfusion.Isolated isovolumic rat hearts were perfused at constant flow (1lmM glucose) and venous oxygen tension continuously monitored. At baseline, tmito was 8.9 f 0.4 s for all groups. At 5 min reperfusion, both reversible (I=5 or 15 min) and irreversible (I=25 min)ischemia resulted in an acceleration: tmito relative to its baseline value was lOOG% (control), 53i8% (I=5 mm). 64t8% (I=15 min) and 51 * 6% (I=25 min). At late reperfusion (>30 mm), reversible ischemia resulted in a slower response: tmito was 114*6% (control), 156?15% (I=Smin) and 153211% (I=15 min), hut not irreversible ischemia (92 f 6%).High perfusate calcium (6mM) deaea~I tmito to 44*11%, whereas blocking mitochondrial calcium uptake (0.1 mg/ml ruthenium red; RR) during the 5min I and early reperfusion diminished the decrease in tmito at 5 min reperfusion (74*5% vs 53t8% without RR), indicating that elevated mito-chondrial [Ca2+] during early reperfusion (~10 min) may partly explain the observed tmito acceleration. Additional studies replacing glucose, before ischemia and during late reperfusion, with substrates used down-stream of glycolysis (11 mM lactate or 11 mM pyruvate), demonstrated no increase in tmito at late reperfusion following 5 min ischemia. The data indicate that reversible ischemia activates glycolysis during reperfusion, and supports the notion that glycolysis plays an important role in the kinetics of the short-term matching of oxygen consumption to demand by delaying the energy-related signal to the mitochondrion. The physiological consequence of the activation of glycolysis in reperfused,reversible ischemic tissue is a slower adaptation of oxygen consumption to changes in workload.

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