Cyclosporine A Preparations and Their Vehicles Induce Contraction of the Guinea Pig Gallbladder in vitro: The Role of Cyclooxygenase Metabolites

Abstract

The aim of this study was to establish whether prostanoids play a role in the contraction induced by cyclosporine A (CyA) preparations in the guinea pig isolated gallbladder strips. It was also aimed to study the effects of the preparations and their solvents on the acetylcholine-evoked rhythmic contractions of the guinea pig isolated sphincter of Oddi (SO). Isometric contractions were recorded. CyA parenteral and oral preparations and their vehicles, Cremophor-EL and Labrafil caused concentration-dependent and sustained contractions (74.2 ± 6.2, 58.4 ± 6.3, 88.9 ± 4.9 and 47.5 ± 6.2% of maximum KCl contraction, respectively) of gallbladder strips, but not of SO. Quinacrine, indometacin and ridogrel inhibited the contraction induced by CyA preparations and their vehicles in gallbladder strips (for CyA parenteral preparation, 34.7 ± 6.7, 1.4 ± 0.9, 19.0 ± 6.4% of maximum KCl contraction, respectively). The drug and its vehicles changed neither the initial contraction nor the amplitude and frequency of the phasic contractions induced by acetylcholine in SO preparations. The results indicate that the drug is able to contract the gallbladder strips and the vehicles contribute to the contracting effect of CyA. Prostanoids may be responsible for the CyA-induced contraction of the gallbladder.

Cyclosporine A-induced acute hepatotoxicity in guinea pigs is associated with endothelin-mediated decrease in local hepatic blood flow

“…We have previously shown the contracting effect of CsA preparations in vitro in guinea-pig isolated gall bladder and the contribution of the vehicles used in CsA preparations, and ET, nitric oxide, and cycloxygenase metabolites to the effect of CsA (Erdem et al 1998;Erdem and Tuncer 2005;Yasar et al 1999). Taking our in vitro data demonstrating the acute smooth muscle contracting effect of CsA into consideration, the present in vivo study tested the hypotheses that CsA induces acute hepatotoxicity in association with the acute decrease in liver perfusion due to vasoconstriction, and that ET contributes to CsA-induced hepatotoxicity.…”