Different acid secretagogues activate different Na1/H1 exchanger isoforms in rabbit parietal cells

Bachmann, O., T. Sonnentag, W.-K. Siegel, G. Lamprecht, A. Weichert, M. Gregor, and U. Seidler. Different acid secretagogues activate different Na1/H1 exchanger isoforms in rabbit parietal cells. Am. J. Physiol. 275 (Gastrointest. Liver Physiol. 38): G1085–G1093, 1998.—Rabbit parietal cells express three Na1/H1 exchanger isoforms (NHE1, NHE2, and NHE4). We investigated the effects of carbachol, histamine, and forskolin on Na1/H1 exchange activity and acid formation in cultured rabbit parietal cells and tested the effect of NHE isoform-specific inhibition on agonist-induced Na1/H1 exchange. Carbachol (1024 M) was the weakest acid secretagogue but caused the strongest Na1/H1 exchange activation, which was completely blocked by 1 μM HOE-642 (selective for NHE1); histamine (1024 M) and forskolin (1025 M) were stronger stimulants of [14C]aminopyrine accumulation but weaker stimulants of Na1/H1 exchange activity. HOE-642 (1 μM) reduced forskolin-stimulated Na1/H1 exchange activity by 35%, and 25 μM HOE-642 (inhibits NHE1 and -2) inhibited an additional 13%, but 500 μM dimethyl amiloride (inhibits NHE1, -2, and -4) caused complete inhibition. The presence of 5% CO2-HCO3 2 markedly reduced agonist-stimulated H1 efflux rates, suggesting that the anion exchanger is also activated. Hyperosmolarity also activated Na1/H1 exchange. Our data suggest that, in rabbit parietal cells, Ca21-dependent stimulation causes a selective activation of NHE1, whereas cAMP-dependent stimulation activates NHE1, NHE2, and more strongly NHE4. Because intracellular pH (pHi) did not change in the presence of CO2HCO3 2 and concomitant activation of Na1/H1 and anion exchange is one of the volume regulatory mechanisms, we speculate that the physiological significance of secretagogueinduced Na1/H1 exchange activation may not be related to pHi but to volume regulation during acid secretion.