Myocardial adaptation during acute hibernation: mechanisms of phosphocreatine recovery.

OBJECTIVES

Acute hibernation, defined as a prolonged period of moderately reduced oxygen supply and stable haemodynamic function, results in metabolic adaptation characterised primarily by an increase in phosphocreatine. The mechanism of this increase in phosphocreatine is unknown, but has been postulated to result from either an increase in adenosine triphosphate (ATP) production or a decrease in ATP utilisation under conditions of constant myocardial oxygen consumption (MVO2). These experiments were performed to test the hypotheses that (1) acute hibernation could be modelled in an isolated perfused rat heart exhibiting metabolic adaptation; and (2) recovery of phosphocreatine could be explained by alterations in relative creatine kinase flux during hibernation.

METHODS

Nuclear magnetic resonance techniques were used in an isolated, perfused rat heart model of acute hibernation to determine the changes in metabolites and creatine kinase kinetics. A flow reduction from 12.5 to 5.4 ml.min-1 was employed for two hours, followed by reperfusion.

RESULTS

Reduction of flow resulted in a stable 44% reduction in rate-pressure product. Phosphocreatine had a significant decrease of 9% within the first 15 minutes of ischaemia, but recovered to control values by the end of ischaemia. ATP and [ADP], although unchanged in the early phase of ischaemia, were progressively reduced during the later phase of ischaemia. Intracellular pH fell from 6.99(0.04) to 6.92(0.03) after 15 minutes of ischaemia with little recovery. Saturation transfer measurements showed stability of the forward flux in the creatine kinase reaction during ischaemia, but a progressive reduction in the calculated reverse flux.

CONCLUSIONS

These data show that acute hibernation can be modelled in an isolated perfused heart, exhibiting recovery of phosphocreatine despite progressive reductions in ATP. Metabolic changes during acute hibernation have a phasic response characterised by an early ischaemic phase and a later adaptive phase. There is a time related change in measured creatine kinase flux, consistent with a differential change in either ATP production via an increase in MB creatine kinase isoenzyme or a shift in the activity of mitochondrial v cytosolic creatine kinase, a reduction in ATP utilisation via increased efficiency of ATP utilisation at the myofibril, or a changing contribution of glycolytically produced ATP.