Effects of Wortmannin, a Novel Myosin Light-Chain Kinase Inhibitor, on Bile Canalicular Contraction in Vitro and in Vivo

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Abstract
Background: The cytoskeletal system is believed to play an important role in normal bile formation. The effects of wortmannin, a new myosin light-chain kinase inhibitor, on bile canalicular contraction and bile flow have been observed. Methods: The bile canalicular contraction of cultured hepatocyte doublets was investigated, using an image analyzer with a phase contrast microscope, and the intracellular Ca2+ concentration was measured, using microscopic fluorometry. We also investigated bile flow by in vivo intraportal infusion of the drug in rats. Results: Treatment with wortmannin inhibited norepinephrine-induced canalicular contraction and caused a decrease in bile flow without changing systemic and portal blood pressure. Morphologic examination of the electron microscopic study showed that most bile canaliculi were dilated, with loss of microvilli, but no other apparent damage was seen in parenchymal hepatocytes. Conclusions: These data suggest that the integrity of the phosphorylation system of myosin is essential for normal bile flow.