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

Marcel Egger and Ernst Niggli

1. The Na⁺-Ca²⁺ exchange is a major pathway for removal of cytosolic Ca²⁺ in cardiac myocytes. It is known to be inhibited by changes of intracellular pH that may occur, for example, during ischaemia. In the present study, we examined whether extracellular protons (pH_o) can also affect the cardiac exchange.

2. Na⁺-Ca²⁺ exchange currents (I_Na-Ca) were recorded from single adult guinea-pig ventricular myocytes in the whole-cell voltage-clamp configuration while [Ca²⁺]_i was simultaneously imaged with fluo-3 and a laser-scanning confocal microscope. To activate I_Na-Ca, intracellular Ca²⁺ concentration jumps 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 I_Na-Ca to 70 % and less than 10 %, respectively. The peak I_Na-Ca was also inhibited to about 45 % of its initial value by increasing pH_o to 10. The largest I_Na-Ca was found at pH_o 7·6.

4. Simultaneous measurements of [Ca²⁺]_i and I_Na-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 observation is consistent with a change in the electrogenicity of the Na⁺-Ca²⁺ exchange cycle after protonation of the transporter.

5. We conclude that both extracellular alkalinization and acidification affect the Na⁺-Ca²⁺ exchanger during changes of pH_o that may be present under pathophysiological conditions. During both extreme acidification or alkalinization the Na⁺-Ca²⁺ exchanger is strongly inhibited, suggesting that extracellular protons may interact with the Na⁺-Ca²⁺ exchanger at multiple sites. In addition, the electrogenicity and stoichiometry of the Na⁺-Ca²⁺ exchange may be modified by extracellular protons.

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