Sodium-Calcium Exchange

Researchers have been aware of the existence of a membrane transporter in cardiac myocytes that exchanged calcium for sodium for more than 30 years.1 In that period of time, even as the molecular details of the sodium-calcium exchanger (NaCaX) were being worked out, its physiological role had still not been clearly defined. Early reports focused on the role of the exchanger as an important source of Ca2+ influx2 and as a regulator of contractile force, an important issue given that the most commonly used inotropic agent at the time was digitalis.3 By the mid-1980s, when it had become clear that Ca2+ entry via L-type Ca2+ channels was the major trigger for contractile Ca2+ release from the sarcoplasmic reticulum (SR), it became widely accepted that the chief role of the exchanger was to remove Ca2+ from the cytosol during diastole. Interest in the exchanger as an important Ca2+ entry mechanism resurfaced early in this decade when LeBlanc and Hume4 demonstrated sodium-current–dependent Ca2+ influx via the exchanger, capable of triggering contraction; however, this idea has remained controversial. Now, as we approach the new millennium and study excitation-contraction (E-C) coupling at the subcellular level,5 6 the importance of the exchanger as a modulator of Ca2+ release and E-C coupling gain is becoming clearer.7 8 The pathophysiological roles of the exchanger have been much less controversial. In the ischemic/reperfused heart, a rise in intracellular sodium9 frustrates the ability of the exchanger to remove Ca2+.10 Stimulation of the exchanger by oxygen free radicals may further accelerate the rise in cell Ca2+ under sodium-loaded conditions.11 The resulting Ca2+ overload is not only detrimental to contractile function, metabolism, and cellular integrity,12 but it is also …