Colchicine does not inhibit secretin-induced choleresis in rats exhibiting hyperplasia of bile ductules: evidence against a pivotal role of exocytic vesicle insertion.
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 proof 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 HCO3- 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 microliters.min-1.kg-1 (p < 0.001) and basal biliary erythritol clearance from 112.7 +/- 6.3 to 69.9 +/- 7.0 microliters.min-1.kg-1 (p < 0.05), it did not significantly affect basal biliary [HCO3-], nor basal biliary bile acid output. Moreover, colchicine did not alter the effects of secretin. Thus, the secretin-induced increments in bile flow, biliary [HCO3-] and biliary HCO3- output averaged 58.2 +/- 13.6 microliters.min-1.kg-1, 16.6 +/- 3.1 mM and 5.3 +/- 1.4 mumol.min-1.kg-1 in vehicle-pretreated controls and 78.4 +/- 12.0 microliters.min-1.kg-1, 16.1 +/- 2.7 mM and 5.1 +/- 0.5 mumol.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.
Dällenbach
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Department of Clinical Pharmacology, University of Berne, Switzerland.
Renner
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EL
D000818:Animals; D001639:Bicarbonates / Q000378:metabolism; D001646:Bile / Q000187:drug effects* / Q000378:metabolism; D001652:Bile Ducts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D003078:Colchicine / Q000494:pharmacology*; D004195:Disease Models, Animal; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology*; D006965:Hyperplasia / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012633:Secretin / Q000502:physiology*
D001639:Bicarbonates; D012633:Secretin; D003078:Colchicine