Early alteration of the control of mitochondrial function in myocardial ischemia

This study was aimed at evaluating the nature of the early mitochondrial alterations in isolated perfused rat hearts subjected to ischemia (37 degrees C, 0.1 ml/min, 15 or 30 min) and reperfusion (10 min). The functional variables of isolated perfused hearts were continuously evaluated, and the mitochondrial respiration variables were determined at the end of protocol on cardiac permeabilized fibers. In a parallel series of experiments, the myocardial contents of inorganic phosphate (Pi), phosphocreatine (PC) and ATP were monitored by means of P-31 NMR spectroscopy for the 15-min ischemia group. Severe mitochondrial alterations were detected in the 30-min ischemia group: decrease of maximal respiration rate and apparent Km for ADP, loss of the stimulatory effect of creatine (Cr) and disruption of the outer membrane. The functional recovery was no more than 10% of the pre-ischemic value. In contrast, in the 15-min ischemia group, only the stimulatory effect of Cr on respiration was significantly decreased. On reperfusion, a restoration of pre-ischemic levels of Pi and PC and a stabilization of the ATP content were observed, demonstrating the establishment of an energy balance steady state. The functional recovery was 76% of pre-ischemic value. We conclude that the alterations related to energy production control (by ADP and Cr) and to energy transfer are the earliest damages to mitochondrial function during ischemia. In spite of a preserved capacity for ATP production, these alterations, which persist on reperfusion, could be responsible for an altered responsiveness of the mitochondrial function to energy demand.