Contribution of protons to post-ischemic Na(+) and Ca(2+) overload and left ventricular mechanical dysfunction.

The intracellular accumulation of Na(+) and Ca(2+) plays a key role in ischemia-induced myocardial injury that may be manifest as left ventricular (LV) mechanical dysfunction, dysrhythmias, or infarction. This review considers the potential contributions of protons (H(+)) produced during ischemia as well as reperfusion to intracellular Na(+) and Ca(2+) homeostasis. ATP hydrolysis produces H(+) and the resulting intracellular acidosis directly impairs LV contractility. However, it is the accumulation of intracellular H(+) and the activation of Na(+)-dependent pH regulatory mechanisms, including the Na(+)-H(+) exchanger (NHE-1) and the Na(+)-HCO(3) (-) cotransporter, which contribute to Na(+) accumulation. Intracellular Na(+) accumulation, coupled with the NHE-1, then causes Ca(2+) overload and further LV mechanical dysfunction. As glycolysis uncoupled from glucose oxidation is an important determinant of the rate of H(+) production, factors that affect glucose metabolism, including degree of ischemia, myocardial workload, and competition from other energy substrates, are expected to influence Na(+) and Ca(2+) accumulation, and hence the recovery of post-ischemic LV mechanical function. Whereas an increase in the uncoupling of glycolysis from glucose oxidation accelerates H(+) production and worsens the recovery of LV mechanical function, inhibition of H(+) production improves recovery of post-ischemic LV mechanical function. Thus, alteration of glucose metabolism, either by inhibition of an excessive rate of glycolysis or by stimulation of glucose oxidation, is an attractive drug target to reduce H(+) production and limit Na(+) and Ca(2+) accumulation and thereby prevent post-ischemic LV dysfunction.