The pathophysiological mechanisms by which brief periods of flow interruption before a prolonged ischemic period, ischemic preconditioning (IPC), increase myocardial tolerance to
ischemia and improve myocardial function during reperfusion are not completely understood. To test whether short periods of metabolic inhibition in the absence of a flow reduction induce similar protective effects, we studied cardiac function and metabolism using 31P nuclear magnetic resonance spectroscopy in isolated isovolumic rat hearts. Fifteen hearts underwent IPC, consisting of two 5-minute
ischemia-reperfusion cycles (IPC group); 18 hearts underwent brief metabolic inhibition by exposure to two 5-minute infusions of 10 mmol/L
sodium cyanide (CN group); and 15 hearts served as controls. Subsequently all hearts were subjected to 30 minutes of total global
ischemia at 37 degrees C followed by reperfusion. At the end of the ischemic period,
creatine phosphate and
ATP levels did not differ among the groups. Cellular pH, however, plateaued at a higher level in the CN group (6.51 +/- 0.03) and IPC group (6.12 +/- 0.06) than in the control group (5.84 +/- 0.01, P < .001). IPC and CN hearts had better functional and metabolic recovery than the control hearts. Improved contractile recovery correlated with coronary flow rates at reperfusion (r = .7, P < .001) and with pHi values at 30 minutes of
ischemia (r = .8, P < .001) but not with increased
ATP levels during
ischemia. Additional control hearts were reperfused at 15 mL/min so as to match the flow rates of IPC and CN groups, but this did not result in improved performance. To test the hypothesis that the preconditioning effect was related to pHi during
ischemia, additional IPC and CN hearts underwent the same preconditioning protocol, except that the cellular pH at the end of the ischemic period was lowered by the use of hypercarbic superfusion during
ischemia or by the use of
bicarbonate-free perfusate just before sustained
ischemia. Both of these interventions resulted in significantly lower contractile and metabolic recoveries than those observed in other IPC and CN hearts. Therefore, the preconditioning effect does not require reduced coronary flow but can be effectively elicited by metabolic inhibition per se in this model. The protective effect is not dependent on preservation of global myocardial energy stores but, rather, on reduced
acidosis during the prolonged ischemic period.