Alpha-2-adrenoceptor hyporesponsiveness in isolated tissues of cholestatic animals: involvement of opioid and nitric oxide systems.
In the present study, the status of alpha(2)-adrenoceptors during cholestasis was investigated by the inhibitory effect of clonidine on the electrically stimulated contractions of mice vas deferens (MVD) and guinea pig ileum (GPI). Clonidine inhibited the contractions in both tissues in a dose-dependent manner. Compared to unoperated animals, there was a significant right-shift in the clonidine concentration-curves of both tissues obtained from 5-day bile-duct ligated (BDL) animals (p < 0.01), implying the hyporesponsiveness of alpha(2)-adrenoceptors during cholestasis. Chronic treatment with naltrexone (3 mg/kg/day) reversed the right-shift induced by cholestasis in both tissues. Administration of N(omega)-nitro-L-arginine methyl ester (20 mg/kg/day) also partially reversed cholestasis-induced effect on IC(50) of clonidine. These two treatments had no effect on IC(50) of tissues from controls. Chronic yohimbine treatment (5 mg/kg/day) recovered the effect of cholestasis on MVD, but sensitized the ileum of unoperated and BDL guinea pigs to clonidine to a similar extent, providing evidence for the role of the augmented adrenergic state of cholestasis in the hyporesponsiveness of norepinephrine-releasing neurons of MVD. We concluded that cholestasis is associated with the decreased responsiveness of alpha(2)-adrenoceptors and the cholestasis-associated augmented opioidergic tone and increased NO production contribute to this process.
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P. O. Box 13145-784, Iran.
Shadpour
S
Demehri
Khodadad
K
Namiranian
Shahram Ejtemaei
SE
Mehr
Hossein
H
Rastegar
Ahamd
A
Shariftabrizi
Seyed Ali
SA
Gaskari
Farshad
F
Roushanzamir
Ahmad Reza
AR
Dehpour
D000818:Animals; D002395:Catecholamines / Q000097:blood; D002779:Cholestasis / Q000503:physiopathology*; D003000:Clonidine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D009271:Naltrexone / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D011957:Receptors, Opioid / Q000502:physiology*; D015016:Yohimbine / Q000494:pharmacology
D002395:Catecholamines; D018341:Receptors, Adrenergic, alpha-2; D011957:Receptors, Opioid; D015016:Yohimbine; D009569:Nitric Oxide; D009271:Naltrexone; D003000:Clonidine