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 pHi was simultaneously acidified to 6.4, the current was transient, dropping by 80% in 30 s. 2. Pre‐exposure to a pHi 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 pHi effects. We observed experimentally that pre‐exposure to acidic pHi 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 & Lederer, 1993b). 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.