DIFFERENT ACID SECRETAGOGUES ACTIVATE DIFFERENT NA+ H+ EXCHANGER ISOFORMS IN RABBIT PARIETAL-CELLS/

Rabbit parietal cells express three Na+/H+ exchanger isoforms (NHE1, N HE2, and NHE4). We investigated the effects of carbachol, histamine, a nd forskolin on Na+/H+ exchange activity and acid formation in culture d rabbit parietal cells and tested the effect of NHE isoform-specific inhibition on agonist-induced Na+/H+ exchange. Carbachol (10(-4) M) wa s the weakest acid secretagogue but caused the strongest Na+/H+ exchan ge activation, which was completely blocked by 1 mu M HOE-642 (selecti ve for NHE1); histamine (10(-4) M) and forskolin (10(-5) M) were stron ger stimulants of [C-14]aminopyrine accumulation but weaker stimulants of Na+/H+ exchange activity. HOE-642 (1 mu M) reduced forskolin-stimu lated Na+/H+ exchange activity by 35%, and 25 mu M HOE-642 (inhibits N HE1 and -2) inhibited an additional 13%, but 500 mu M dimethyl amilori de (inhibits NHE1, -2, and -4) caused complete inhibition. The presenc e of 5% CO2-HCO3- markedly reduced agonist-stimulated H+ efflux rates, suggesting that the anion exchanger is also activated. Hyperosmolarit y also activated Na+/H+ exchange. Our data suggest that, in rabbit par ietal cells, Ca2+-dependent stimulation causes a selective activation of NHE1, whereas cAMP-dependent stimulation activates NHE1, NHE2, and more strongly NHE4. Because intracellular pH (pH(i)) did not change in the presence of CO2-HCO3- and concomitant activation of Na+/H+ and an ion exchange is one of the volume regulatory mechanisms, we speculate that the physiological significance of secretagogue-induced Na+/H+ exc hange activation may not be related to pH(i) but to volume regulation during acid secretion.