Effects of pH on Na+-Ca2+ exchange in canine cardiac sarcolemmal vesicles

Using highly purified sarcolemmal vesicles isolated from dog ventricles, we examined the effects of pH on Na+-Ca2+ exchange. The initial rate of Nai+-dependent Ca2+ uptake is a sigmoid function of pH. The Ca2+ uptake is inhibited at pH 6 and stimulated at pH 9 (as compared with uptake at pH 7.4). This dependence on pH suggests that the ionization state of a histidine residue may be important in Na+-Ca2+ exchange. The effects of H+ on Nai+-dependent Ca2+ uptake are partially competitive with Ca2+, although this relationship is complex. Nao+-dependent Ca2+ efflux is also sensitive to H+ and increases monotonically with pH. These effects of pH appear to be due to intrinsic interactions with the Na+-Ca2+ exchange system and are not due to an alteration of Na+-H+ exchange or membrane permeability. The effects of pH on vesicular Na+-Ca2+ exchange are apparent only at low Ca2+ and Na+ concentrations. Thus modulation of vesicular Na+-Ca2+ exchange by pH is manifest only under ionic conditions which exist intracellularly in intact myocardium. Since the negative inotropy caused by acidosis is thought to reflect a fall in internal pH, these results suggest that alteration of sarcolemmal Ca2+ transport (medicated by Na+-Ca2+ exchange) by internal pH may contribute to the regulation of myocardial contractility by pH.