Ca2+‐activated K+ channels mediate duodenal mucosal bicarbonate secretion

Abstract

Duodenal mucosal bicarbonate secretion (DMBS) is currently accepted as a primary defense process against gastric acid, but the precise mechanism of DMBS has not been completely elucidated. The aim of the present study was to determine whether Ca2+-activated K+(KCa) channels are expressed in the duodenal mucosa and whether they are involved in Ca2+-mediated DMBS. DMBS was determined in vitro by pH-stat and in vivo by using a CO2-sensitive electrode. Expression of KCa in duodenal mucosae was analyzed by RT-PCR. Clotrimazole (30 μM), a selective blocker for intermediate KCa channels (IKCa), significantly inhibited carbachol (CCh)-induced DMBS, but did not affect forskolin-induced or heat-stable enterotoxin of Escherichia coli (STa)-induced DMBS. TRAM-34 (10 μM), another more potent and selective IKCa channel blocker, also significantly inhibited CCh-induced DMBS. However, tetraethylammonium, 4-aminopyridine, and BaCl2, at concentrations known to block K+ channels other than IKCa, failed to inhibit CCh-induced DMBS. A23187 (10 μM), a Ca2+ ionophore, and 1-EBIO (1 mM), a selective opener of KCa channels, increased DMBS markedly more pronounced following serosal vs. mucosal addition. Again, both clotrimazole and TRAM-34 significantly reduced A23187- or 1-EBIO-induced DMBS. Finally, duodenal luminal perfusion with 10 mM HCl increased DMBS in vivo, which was inhibited by 77% when mice were injected (i.p.) with 20 mg/kg clotromazole. Expression of mRNA for IKCa channels was also detected in mouse duodenal mucosae by RT-PCR analysis. Our results imply an important role for IKCa in murine DMBS. An increase in [Ca2+]i induced by cholinergic neurotransmitters may activate DMBS secondary to opening of basolateral IKCa, thereby maintaining energetics favorable for duodenal HCO3− secretion.