Na+/Ca++ exchanger and myocardial ischemia/reperfusion.

Abstract

Myocardial hypoxia and ischemia are characterized by the depletion of ATP and the development of intracellular acidosis, which alter cellular ionic homeostasis. Specifically, elevated cytosolic free Ca++ concentrations cause cellular injury during hypoxia/ischemia and lead to irreversible myocardial damage during reoxygenation/reperfusion. An increase in the intracellular Na+ concentration has been shown to correlate with Ca++ overload. Although inhibition of Na+/K+ exchange because of decreased ATP production may be involved, it is more likely that intracellular acidosis drives Na+ into the cells via Na+/H+ exchange. Experimental evidence supports the notion that Na+/H+ exchange is primarily responsible for Na+ influx during hypoxia/ischemia. The accumulation of intracellular Na+ may then activate the Na+/Ca++ exchanger causing Ca++ overload. Therefore, the Na+/Ca++ exchanger plays a crucial role in cellular injury during hypoxia/ischemia and in cell death during reoxygenation/reperfusion. In the past few years, the Na+/Ca++ exchanger has been cloned and the structure/function relationship studied intensively. Agents which inhibit the Na+/Ca++ exchanger may have therapeutic potential for the treatment of ischemic heart disease. These advances will greatly accelerate the understanding of the cellular and molecular mechanisms underlying the role of the Na+/Ca++ exchanger in the development of myocardial damage during hypoxia/ischemia and reoxygenation/reperfusion.