Identification of Na-Ca exchange current in single cardiac myocytes

Abstract

In cardiac muscle the exchange of intracellular Ca²⁺ for extracellular Na⁺ is an important transport mechanism for regulation of the intracellular free Ca²⁺ concentration ([Ca]_i) and hence the contractile strength of the heart (ref. 1 ; for reviews see refs 2–4). Due to its stoichiometry of ≥3:l Na⁺/Ca²⁺ (refs 3,5), Na-Ca exchange is supposed to generate a current across the cell membrane. It is thought that such a current may contribute to cardiac action potential and physiological or pathological pacemaker activity^6,7. Although the occurrence of Na-Ca exchange is well documented, a membrane current generated by this transport has not been identified unequivocally. Previous attempts to detect such a current-in multicellular preparations, for example, by measuring small current differences after varying the extracellular ionic composition⁸, although providing evidence, did not rule out other possible interpretations. Here we demonstrate that a transient rise in [Ca]_i caused by release of Ca from sarcoplasmic reticulum (SR) generates a membrane current in cardiac myocytes. The dependence of this current on the transmembrane gradients for Na⁺ and Ca²⁺ and on membrane potential meets the criteria for a current produced by electrogenic Na-Ca exchange. Cyclic activation of this current by release of Ca from the SR can cause maintained spontaneous activity, suggesting that Na-Ca exchange contributes to certain forms of cardiac pacemaking.