Myocardial energetics and the recovery of contractile function following ischemia and reperfusion in the isolated perfused rabbit heart.

Abstract

I hypothesized that a significant component of myocardial contractile dysfunction following ischemia in the isolated rabbit myocardium is the result of insufficient energy (ATP) production, and that functional recovery may be enhanced by increasing ATP synthesis. The data showed that contractile recovery was independent of intracellular pH, ATP, or phosphocreatine concentrations. My results also suggest that functional recovery correlates with increased ATP synthesis accompanied by increased ATP utilization. Preischemic administration of adenosine improved contractile recovery after severe ischemia. Adenosine's beneficial action was not mediated by A$\sb1$- and A$\sb2$-receptors or by adenylate cyclase, but pharmacologically blocking adenosine entry into cells prevented recovery. Preventing adenosine phosphorylation by inhibiting adenosine kinase diminished recovery, suggesting recovery was mediated through adenosine incorporation into the adenine nucleotide pool. Purine loss after ischemia was decreased by interventions that enhanced purine salvage, and increased when purine salvage was prevented. The size of the total adenine nucleotide pool (AMP + ADP + ATP) correlated with functional recovery, consistent with increased purine salvage, but ATP concentration alone did not. Following less severe ischemic insults, increasing purine salvage had only modest effects on contractile recovery. On the basis of my research, I accept the hypothesis that a significant component of contractile dysfunction after ischemia is the result of insufficient ATP production, and postischemic function is improved by increasing ATP synthesis.