Sodium calcium exchange in the heart: necessity or luxury?

The sodium calcium exchange (NCX) was first discovered in cardiac muscle1 and squid axon2 and has since been found in most cell types (see reviews3,4). It accounts for the previously observed effects of sodium on cardiac contractility.5 The exchanger transports 3 Na ions per Ca .6–8 This stoichiometry has three important consequences.1 Ca fluxes and hence intracellular Ca concentration ([Ca ]i) are very sensitive to intracellular Na concentration ([Na ]i), and therefore, even small changes of [Na ]i have large effects on contractility. In the case of vascular smooth muscle, the [Na ]i-dependence of NCX has been suggested to account for aspects of hypertension.102 The activity of NCX is affected by membrane potential with depolarization hindering Ca efflux and increasing Ca influx. This voltage dependence may produce net Ca entry into the cell at the start of the action potential and contribute to triggering Ca -induced Ca release from the sarcoplasmic reticulum (SR)11 (although the NCX is a much weaker trigger of Ca release than is the L-type Ca current12).3 Changes in the activity of NCX attributable to an increase in [Ca ]i activate inward current. Specifically, (1) inward current activated by the systolic Ca transient will contribute to maintaining the action potential plateau,13 and (2) current activated by abnormal Ca release in diastole generates14,15 the delayed afterdepolarizations known to be a cause of triggered arrhythmias.16–18