Basolateral Ca2+-dependent K+-channels play Cl-secretion induced by taurodeoxycholate from a key role in colon mucosa

The diarrhea associated with malabsorption of bile salts such as the secondary hydrophobic taurodeoxycholate (TDC) may be partly explained by the TDC-induced increase in colon Cl- secretion. We, therefore, investigated the effects of TDC (0.5-8 mM) on electrical parameters and electrolyte transport of rat proximal colon mucosa mounted in Ussing chambers. Colonic secretion, measured as short circuit current (I-SC), progressively increased on mucosal incubation with TDC ranging 0;5-2 mM; up to TDC 2 mM, a spontaneous recovery toward control values with no changes in epithelial resistance (Rt), and lactate dehydrogenase (LDH) release was observed. In contrast, for TDC > 2 mM, Is, increased future and the effect was progressive and associated with a significant decrease in the Rt and increased LDH release, implying a cytolytic effect. Mucosal preincubation with the Cl- channel inhibitor 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB), fully prevented the precytolytic effect of TDC on I-SC. Serosal preincubation with furosemide, a Na+/K+/2Cl(-) cotransporter inhibitor, significantly reduced TDC-induced increase in I-SC. Inhibition of the basolateral Ca2+-dependent K+ channel-rSK4-with serosal clotrimazole or incubation with mucosal Ca2+-free (EGTA) buffer completely prevented precytolytic TDC-induced increase in I-SC. In conclusion, Cl- secretion is activated in colon mucosa by TDC low concentrations; while at higher concentrations, a detergent cytotoxic effect intervenes. Activation of the Ca2+-dependent basolateral K+ pathway, through TDC-induced apical Ca2+ influx, provides the Na+/K+/2Cl(-) basolateral activation, thereby the driving force for the apical exit of Cl- ions. These findings further enhance the knowledge of the pathogenic mechanisms of diarrhea associated with bile salt malabsorption. (C) 2003 Editions scientifiques et medicales Elsevier SAS. All rights reserved.