Creatine Kinase of Heart Mitochondria. The Progressive Loss of Enzyme Activity During in Vivo Ischemia and Its Correlation to Depressed Myocardial Function

It is now appreciated that mitochondrial creatine kinase (CKm) may play an important role in heart high-energy phosphate metabolism and that this isozyme is solubilized in vitro by dilute solutions of Pi. Since an increase in cellular Pi is known to occur with even brief periods of myocardial ischemia, we investigated the relationship between CKm activity and myocardial performance in rabbit hearts subjected to total global ischemia. CKm activity is expressed as a ratio to mitochondrial malate dehydrogenase (MDHm), a stable marker enzyme. A significant decline in this ratio was observed after only 10 min of ischemia, a time prior to changes in total homogenate creatine kinase activity. After 60 min of ischemia, the CKm/MDHm ratio was depressed by more than 70%. Since there was no restoration of activity following 30 min of reperfusion, we correlated changes in enzyme activity to contractile dysfunction following variable periods of total ischemia. The data showed a close correlation between the decline in the CKm/MDHm ratio and the reduction in performance, measured as left ventricular developed pressure. No correlation was observed between State 3 respiratory rates and performance. Using KCl arrest at 27 degrees C or hyperthermic ischemia at 40 degrees C, the CKm/MDHm ratio consistently correlated to the degree of postischemic functional depression, independent of the duration of ischemia. Isoenzyme electrophoresis failed to detect soluble CKm activity in the postischemic supernatant. Therefore, CKm activity appears to be altered rapidly and irreversibly by ischemia. The implications of these observations on the integration of myocardial high-energy phosphate metabolism are discussed.