95 Bicarbonate-rich choleresis induced by secretin in normal rat is taurocholate dependent and involves AE2 anion exchanger

Abstract

Canalicular bile is modified along bile ducts through reabsorptive and secretory processes regulated by nerves, bile salts, and hormones such as secretin. Secretin stimulates ductular cystic fibrosis transmembrane conductance regulator (CFTR)–dependent Cl efflux and subsequent biliary HCO3 secretion, possibly via Cl /HCO3 anion exchange (AE). However, the contribution of secretin to bile regulation in the normal rat, the significance of choleretic bile salts in secretin effects, and the role of Cl /HCO3 exchange in secretin-stimulatedHCO3 secretion all remainunclear.Here, secretinwas administered tonormal ratswithmaintainedbile acidpool via continuous taurocholate infusion. Bile flow and biliary HCO3 and Cl excretion were monitored following intrabiliary retrograde fluxes of saline solutions with and without the Cl channel inhibitor 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB) or the Cl /HCO3 exchange inhibitor 4,4 -diisothiocyanatostilbene-2,2 -disulfonic acid (DIDS). Secretin increased bile flow and biliary excretion ofHCO3 andCl . Interestingly, secretin effects were not observed in the absence of taurocholate.Whereas secretin effects were all blocked by intrabiliary NPPB, DIDS only inhibited secretin-induced increases in bile flow and HCO3 excretion but not the increased Cl excretion, revealing a role of biliary Cl /HCO3 exchange in secretininduced, bicarbonate-rich choleresis in normal rats. Finally, small hairpin RNA adenoviral constructs were used to demonstrate the involvement of the Na -independent anion exchanger 2 (AE2) through gene silencing in normal rat cholangiocytes. AE2 gene silencing caused amarked inhibition of unstimulated and secretin-stimulated Cl /HCO3 exchange. In conclusion, maintenance of the bile acid pool is crucial for secretin to induce bicarbonate-rich choleresis in the normal rat and that this occurs via a chloride–bicarbonate exchange process consistent with AE2 function. (HEPATOLOGY 2006;43:266-275.)