Basolateral Ca²⁺-dependent K⁺-channels play a key role in C1^- secretion induced by taurodeoxycholate from 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, I_sc increased further 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.