A2-adrenoceptor subsensitivity in mesenteric vascular bed of cholestatic rats : The role of nitric oxide and endogenous opioids

Abstract Cholestasis is associated with vascular changes and in previous studies decreased response of visceral vessels of cholestatic animals to phenylephrine and acetylcholine has been shown. In the present study, the response of mesenteric vascular bed of cholestatic rats to clonidine (an α 2 -adrenoceptor agonist) was investigated and we also examined the role of endogenous opioids and nitric oxide (NO). Seven-day ligation of bile duct was used as the model to study cholestasis. Six groups of rats, each of which divided into two subgroups (bile duct-ligated and sham-operated), were examined. Three groups of animals were chronically treated with either normal saline, naltrexone (an opioid receptor antagonist, 20 mg/kg/day, s.c.) or aminoguanidine (a selective inducible nitric oxide synthase inhibitor, 150 mg/kg/day, s.c.) for 7 days. After 7 days the response of the mesenteric vascular bed to subsequent doses of clonidine was studied. In other two groups, 7 days after the operation, the response of the mesenteric vascular bed to clonidine in the presence of either yuhimbine, an α 2 -adrenoceptor antagonist, or N (ω)-nitro- l -arginine methyl ester ( l -NAME), a non-selective nitric oxide synthase inhibitor, was studied. In the last group, vasodilation response to sodium nitroprusside (an endothelium-independent vasorelaxant) was evaluated. Clonidine caused vasodilation in a dose-dependent manner by acting on endothelial α 2 -adrenoceptors since its effect was antagonized by yohimbine, and this vasodilation was through the l -arginine pathway since there was no response in the presence of l -NAME in the perfusate. Compared to sham-operated rats, there was a significant right shift in the clonidine concentration curves of cholestatic animals. Maximum response in cholestatic rats was significantly lower comparing to the sham group ( P 50 ) was significantly higher in cholestatic rats ( P P 50 ( P P 50 ( P