The source and fate of protons in postischemic hearts

Introduction. Intracellular acidosis is one of the major triggers for ischemia/reperfusion injury. This is because the Na+/H + exchanger (NHE1) is activated during reperfusion, resulting in intracellular Na+ and Ca2+ overload. High rates of fatty acid oxidation during reperfusion may contribute to NHE1 activation by increasing proton (H+) production due to an uncoupling of glycolysis with glucose oxidation. This is associated with poor recovery of cardiac function and efficiency. The present studies determined if increased H+ production delays the recovery of intracellular pH (pH_i) during reperfusion and whether reducing H+ production or inhibiting NHE1 can improve the recovery of cardiac function and efficiency.; Methods. An isolated working heart model for measurement of pH_i by 31P-NMR was developed. Hearts perfused with [5-3H/U-14C]glucose (5.5 mM) ± [1- 14C]palmitate (1.2 mM) were subjected to 30 min aerobic perfusion, 20 min of global no-flow ischemia and 40 or 50 min of reperfusion.; Results. In the presence of palmitate, glucose oxidation was inhibited, causing an increased H+ production from uncoupled glucose metabolism. Treatment with T₃ stimulated glucose oxidation, reduced H+ production and improved the recovery of cardiac function and efficiency. If hearts were perfused with glucose alone, or with dichloroacetate (to stimulate glucose oxidation), which significantly reduced H+ production by improving the coupling of glucose metabolism, accelerated pH_i recovery and improved recovery of cardiac function and efficiency were seen during reperfusion. Inhibition of NHE1 by cariporide also improved the recovery of cardiac function and efficiency, despite a slower recovery of pH_i. H₂O₂ did not decrease pH _i by improving the coupling of glucose metabolism.; Conclusion. An increased H+ production generated from uncoupled glucose metabolism, due to the presence of a high level of fatty acid, significantly delays the recovery of pH_i during reperfusion and contributes to the poor recovery of cardiac function and efficiency. Either reducing H+ production or inhibition of NHE1 improves the recovery of cardiac efficiency and contractile function. The recovery of pH_i per se is not critical for the recovery of cardiac mechanical function and efficiency. It is the clearance of H+ via the NHE1 that contributes to ischemia/reperfusion injury.