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

Myocardial hypoxia and ischemia are characterized by the depletion of ATP a nd the development of intracellular acidosis, which alter cellular ionic ho meostasis. Specifically, elevated cytosolic free Ca++ concentrations cause cellular injury during hypoxia/ischemia and lead to irreversible myocardial dam-. age during reoxygenation/reperfusion. An increase in the intracellul ar Naf concentration has been shown to correlate with Ca++ overload. Althou gh inhibition of Na+/K+ exchange because of decreased ATP production may be involved, it is more likely that intracellular acidosis drives Na+ into th e cells via Na+/H+ exchange. Experimental evidence supports the notion that Na+/H+ exchange is primarily responsible for Na+ influx during hypoxia/isc hemia. 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++ excha nger has been cloned and the structure/function relationship studied intens ively. Agents which inhibit the Na+/Ca++ exchanger may have therapeutic pot ential for the treatment of ischemic heart disease. These advances will gre atly accelerate the understanding of the cellular and molecular mechanisms underlying the role of the Na+/Ca++ exchanger in the development of myocard ial damage during hypoxia/ischemia and reoxygenation/reperfusion.