Protective effect of carvedilol on chenodeoxycholate induction of the permeability transition pore

Intracellular accumulation of toxic, hydrophobic bile acids has been propos ed as one of the putative final common pathways leading to cholestatic live r injury. Furthermore, bile acids have been proposed as a causative factor for hepatic cardiomyopathy. Hepatic tissue concentrations of chenodeoxychol ic acid (CDCA) during cholestasis are greater than those of other toxic bil e acids. In the presence of calcium and phosphate, CDCA induced the permeab ility transition pore (PTP) in freshly isolated rat liver mitochondria. In this study, we evaluated the effects of carvedilol, a multirole cardioprote ctive compound, on CDCA-induced PTP. Mitochondrial membrane potential, osmo tic swelling, and calcium fluxes were monitored. CDCA-induced PTP, characte rized by membrane depolarization, release of matrix calcium, and osmotic sw elling, was prevented by carvedilol. Under the same conditions, its hydroxy lated analog BM-910228 did not reveal any protective effect. This finding r einforces carvedilol's therapeutic interest, because it may potentially pre vent mitochondrial dysfunction associated with cardiomyopathy in the pathop hysiology of cholestatic liver disease. (C) 2001 Elsevier Science Inc. All rights reserved.