Modulation of sodium/calcium exchange: a hypothetical positive inotropic mechanism

The Na+/Ca2+ exchange carrier is a major process for Ca2+ extrusion from cardiac cells. From the stoichiometry of ion translocation in sarcolemmal vesicles, the Na+/Ca2+ exchange is considered to be electrogenic and therefore depends not only on ion concentration gradients but also on membrane potential. Hence Ca2+ entry via the Na+/Ca2+ exchange is also at least theoretically possible. Under certain conditions, the countertransport could contribute to enhancement of force of contraction either by inhibiting Ca2+ efflux or by promoting Ca2+ entry. However, at present it is impossible to predict unequivocally the direction in which the exchanger will work in the course of the cardiac excitation cycle. This is why despite the discovery of many inhibitors and stimulators of Na+/Ca2+ exchange in sarcolemmal vesicles their effects in intact heart muscle are often surprising. Only a small number of agents are sufficiently effective in modifying Na+/Ca2+ exchange activity, but they are by no means selective and influence other ion-transporting systems as well. At present, these substances are of experimental interest as tools in the study of the characteristics of the Na+/Ca2+ exchange. In conclusion, pharmacological modification of the Na+/Ca2+ exchange seems to have potential influence on cardiac force of contraction. However, before this principle can be introduced into therapy, more detailed knowledge is required about the physiological function of the countertransport, more specific drugs must be developed, and more information is needed about possible simultaneous effects on Na+/Ca2+ exchange in other tissues, such as vascular smooth muscle.