Colchicine does not inhibit secretin-induced choleresis in rats exhibiting hyperplasia of bile ductules: evidence against a pivotal role of exocytic vesicle insertion

Abstract

Based on studies in the pig, secretin choleresis has been proposed to be initiated by colchicine-inhibitable, exocytic insertion into the basolateral cholangiocyte membrane of intracytoplasmatic vesicles containing a H+ ATPase. Formal prof of this hypothesis in the intact liver of other species, however, is lacking. The effect of the microtubule inhibitor colchicine on the ductular bile formation and HCO−3 secretion induced by secretin was, therefore, explored in a secretin-responsive rat model characterized by marked hyperplasia of bile ductules.While colchicine pretreatment significantly decreased basal bile flow from 142.1±8.8 to 83.4±8.2 μl· min−1·kg−1 (p<0.001) and basal biliary erythritol clearance from 112.7±6.3 to 69.9±7.0 μl·min−1. kg−1 (pš0.05), it did not significantly affect basal biliary [HCO−3], nor basal biliary bile acid output. Moreover, colchicine did not alter the effects of secretin. Thus, the secretin-induced increments in bile flow, biliary [HCO−3] and biliary HCO−3 output averaged 58.2±13.6 μl·min−1·kg−1, 16.6±3.1 mM and 5.3±1.4 μmol·min−1·kg−1 in vehicle-pretreated controls and 78.4±12.0 μl·min−1·kg−1, 16.1±2.7 mM and 5.1±0.5 μmol·min−1·kg−1 in colchicine-pretreated animals (all p values=n.s), respectively. This suggests that, at least in the rat model used, microtubule-dependent mechanisms are involved in basal, bile acid independent canalicular, but not in secretin-induced ductular, bile formation. Inasmuch as microtubule-dependent mechanisms are required for vesicle movement, this argues strongly against an absolute requirement for exocytic vesicle insertion in the ductular choleresis induced by secretin.