Paradoxical block of the Na+-Ca2+ exchanger by extracellular protons in guinea-pig ventricular myocytes

1. The Na+-Ca2+ exchange is a major pathway for removal of cytosolic Ca2+ i n cardiac myocytes. It is known to be inhibited by changes of intracellular pH that, may occur, for example, during ischaemia. In the present study, w e examined whether extracellular protons (pH(o)) can also affect the cardia c exchange. 2. Na+-Ca2+ exchange currents (INa-Ca) were recorded from single adult guin ea-pig ventricular myocytes in the whole-cell voltage-clamp configuration w hile [Ca2+](i) was simultaneously imaged with fluo-3 and a laser-scanning c onfocal microscope. To activate INa-Ca intracellular Ca2+ concentration jum ps were generated by laser flash photolysis of caged Ca2+ (DM-nitrophen). 3. Exposure of the cell to moderately and extremely acidic conditions (pH(o ) 6 and 4) was accompanied by a decrease of the peak INa-Ca to 70 % and les s than 10 %, respectively. The peak INa-Ca was also inhibited to about 45 % of its initial value by increasing pH(o) to 10. The largest INa-Ca was fou nd at pH(o) approximate to 7.6. 4. Simultaneous measurements of [Ca2+](i) and INa-Ca during partial proton block of the Na+-Ca2+ exchanger revealed that the exchange current was more inhibited by acidic pH(o) than the rate of Ca2+ transport. This observatio n is consistent with a change in the electrogenicity of the Na+-Ca2+ exchan ge cycle after protonation of the transporter. 5. We conclude that both extracellular alkalinization and acidification aff ect the Na+-Ca2+ exchanger during changes of pH(o) that may be present unde r pathophysiological conditions. During both extreme acidification or alkal inization the Na+-Ca2+ exchanger is strongly inhibited, suggesting that ext racellular protons may interact with the Na+-Ca2+ exchanger at multiple sit es. In addition, the electrogenicity and stoichiometry of the Na+-Ca2+ exch ange magi be modified by extracellular protons.