Stimulation of bile duct epithelial secretion by glybenclamide in normal and cholestatic rat liver

The Journal of Clinical Investigation
Michael H NathansonL Rios-Velez

Abstract

Cholestasis is a cardinal complication of liver disease, but most treatments are merely supportive. Here we report that the sulfonylurea glybenclamide potently stimulates bile flow and bicarbonate excretion in the isolated perfused rat liver. Video-microscopic studies of isolated hepatocyte couplets and isolated bile duct segments show that this stimulatory effect occurs at the level of the bile duct epithelium, rather than through hepatocytes. Measurements of cAMP, cytosolic pH, and Ca2+ in isolated bile duct cells suggest that glybenclamide directly activates Na+-K+-2Cl- cotransport, rather than other transporters or conventional second-messenger systems that link to secretory pathways in these cells. Finally, studies in livers from rats with endotoxin- or estrogen-induced cholestasis show that glybenclamide retains its stimulatory effects on bile flow and bicarbonate excretion even under these conditions. These findings suggest that bile duct epithelia may represent an important new therapeutic target for treatment of cholestatic disorders.

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Citations

Aug 4, 2001·The Biochemical Journal·M H NathansonN F Larusso
Oct 7, 2006·Current Opinion in Gastroenterology·R T Prall, N F Larusso
Mar 11, 2005·Journal of Clinical Gastroenterology·Mario StrazzaboscoCarlo Spirli
Jan 13, 2009·American Journal of Physiology. Gastrointestinal and Liver Physiology·Jin YuJonathan A Dranoff
Dec 17, 2008·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Tsunehiro ShintaniMakoto Suematsu
Jul 13, 2011·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Emma A KruglovMichael H Nathanson
Oct 6, 2007·Gastroenterology·Noritaka MinagawaMichael H Nathanson
Feb 24, 2004·The Journal of Physiology·M Paz Fernández-SalazarJosé I San Román
Jun 15, 2006·World Journal of Gastroenterology : WJG·Noritaka MinagawaMichael-H Nathanson
Nov 8, 2014·The Journal of Biological Chemistry·Meenakshisundaram AnanthanarayananMichael H Nathanson
Jul 12, 2001·American Journal of Physiology. Gastrointestinal and Liver Physiology·S K SinghJ L Boyer
Jan 16, 1999·Biochimica Et Biophysica Acta·S PedersenE K Hoffmann
Aug 7, 2001·Gastroenterology·K Hirata, M H Nathanson

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