THE ACTION OF NA+ AS A COFACTOR IN THE INHIBITION BY CYTOPLASMIC PROTONS OF THE CARDIAC NA+-CA2+ EXCHANGER IN THE GUINEA-PIG

1. Na+-Ca2+ exchange current was activated in giant excised patches of guinea-pig cardiac sarcolemma by raising the intracellular sodium concentration ([Na+](i)). When the pH(i) was simultaneously acidified to 6.4, the current was transient, dropping by 80% in 30 s. 2. Pre-exposure to a pH(i), of 6.4 for 15 s reduced the peak Na+-Ca2+ exchange current without altering the decay rate or steady-state current. Recovery from proton inhibition was seen when [Na+](i) was removed for 9 s. 3. A mathematical model of Na+-Ca2+ exchange function reproduced the experimental results. In addition, two model-dependent predictions were seen experimentally. (i) [Na+](i)-dependent 'inactivation' of Na+-Ca2+ exchange may arise from pH(i) effects. We observed experimentally that pre-exposure to acidic pH(i) can remove the transient current component attributed to [Na+](i)-dependent 'inactivation'. (ii) Self-exchange should be inhibited by acidification. This has been observed by other investigators. 4. We have hypothesized that there are two components to inhibition of the Na+-Ca2+ exchanger by intracellular protons, and that one is enhanced by increased [Na+](i) (Doering and Lederer, 1993 b). This hypothesis is supported by the data presented here and by a model of Na+-Ca2+ exchange behaviour in which binding of intracellular sodium to the exchanger enhances the affinity of the exchanger for inhibitory intracellular protons.