Bicarbonate and butyrate stimulate electroneutral Na absorption via apical membrane Na-H exchange (NHE) in rat distal colon. cAMP downregulates NHE-3 isoform and inhibits HCO 3 -dependent, but not butyrate-dependent, Na absorption. This study sought to determine whether 1 ) the apical membrane NHE-2 and NHE-3 isoforms differentially mediated HCO 3 - and butyrate-dependent Na absorption, and 2 ) cAMP had different effects on NHE-2 and NHE-3 isoforms. The effect of specific inhibitors of NHE-2 and NHE-3 isoforms (50 µM HOE 694 and 2 µM S3226, respectively) on unidirectional 22 Na transepithelial fluxes performed across isolated mucosa from rat distal colon under voltage-clamp conditions was examined. HCO 3 stimulation of Na absorption was inhibited by EIPA, a nonspecific inhibitor of all NHE isoforms, by S3226 and dibutyryl cAMP but not by HOE 694. In contrast, butyrate stimulation of Na absorption was not altered by dibutyryl cAMP and was not inhibited by HOE 694 in the absence of dibutyryl cAMP, but in the presence of dibutyryl cAMP was HOE694 sensitive. In contrast, S3226 inhibited butyrate-stimulated Na absorption in the absence of dibutyryl cAMP, but not in its presence. We conclude that 1 ) HCO 3 -stimulated Na absorption is mediated solely by NHE-3 isoform, whereas butyrate-stimulated Na absorption is mediated by either NHE-3 or NHE-2 isoform, and 2 ) dibutyryl cAMP selectively inhibits NHE-3 isoform but stimulates NHE-2 isoform. Dibutyryl cAMP does not inhibit butyrate-stimulated Na absorption as a result of its differential effects on NHE-2 and NHE-3 isoforms. butyrate-dependent Na absorption; HCO 3 -dependent Na absorption; specific NHE isoform inhibitors; NHE-2 isoform; NHE-3 isoform Address for reprint requests and other correspondence: H. J. Binder, Yale Univ., Dept. of Internal Medicine, PO Box 208019, New Haven, CT 06520-8019 (E-mail: firstname.lastname@example.org ).
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