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 (Isc), 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, Isc 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 Isc. Serosal preincubation with furosemide, a Na+/K+/2Cl- cotransporter inhibitor, significantly reduced TDC-induced increase in Isc. 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 Isc. 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.
|Number of pages||8|
|Journal||Biology of the cell / under the auspices of the European Cell Biology Organization|
|Publication status||Published - Mar 2003|
- Bile salts
- Mucosal transport
ASJC Scopus subject areas
- Cell Biology