α2-adrenoceptor subsensitivity in mesenteric vascular bed of cholestatic rats: The role of nitric oxide and endogenous opioids

Amir Ali Borhani, Golbahar Houshmand, Morteza Samini, Khodadad Namiranian, Amir R. Hajrasouliha, Sina Tavakoli, Farzad Ebrahimi, Ahmad Raza Dehpour

Research output: Contribution to journalArticle

10 Citations (Scopus)

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 α2-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 α2- 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 α2-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 < 0.01) and the dose of clonidine that causes 50% of maximum response (ED 50) was significantly higher in cholestatic rats (P < 0.05). Vasodilation response to sodium nitroprusside was the same in cholestatic and sham-operated rats. Seven-day treatment with aminoguanidine recovered the effect of cholestasis. Seven-day treatment with naltrexone caused an increase in maximum response (P < 0.01) and a decrease in ED50 (P < 0.05) in cholestatic rats, while this treatment in sham-operated rats caused a decrease in the maximum response (P < 0.01) and an increase in ED 50 (P < 0.05). This study showed that cholestasis is associated with decreased responsiveness of mesenteric vascular bed to clonidine and the cholestasis-associated NO overproduction and increased level of endogenous opioids may contribute to this process.

Original languageEnglish (US)
Pages (from-to)183-189
Number of pages7
JournalEuropean Journal of Pharmacology
Volume514
Issue number2-3
DOIs
StatePublished - May 9 2005
Externally publishedYes

Fingerprint

Clonidine
Adrenergic Receptors
Opioid Analgesics
Blood Vessels
Nitric Oxide
Cholestasis
Vasodilation
Naltrexone
Nitroprusside
Bile Ducts
Yohimbine
Narcotic Antagonists
Phenylephrine
Nitric Oxide Synthase Type II
Vasodilator Agents
Nitric Oxide Synthase
Acetylcholine
Endothelium
Ligation
Arginine

Keywords

  • α-Adrenoceptor
  • Cholestasis
  • Clonidine
  • Mesenteric vascular bed
  • Nitric oxide
  • Opioid

ASJC Scopus subject areas

  • Pharmacology

Cite this

α2-adrenoceptor subsensitivity in mesenteric vascular bed of cholestatic rats : The role of nitric oxide and endogenous opioids. / Borhani, Amir Ali; Houshmand, Golbahar; Samini, Morteza; Namiranian, Khodadad; Hajrasouliha, Amir R.; Tavakoli, Sina; Ebrahimi, Farzad; Dehpour, Ahmad Raza.

In: European Journal of Pharmacology, Vol. 514, No. 2-3, 09.05.2005, p. 183-189.

Research output: Contribution to journalArticle

Borhani, Amir Ali ; Houshmand, Golbahar ; Samini, Morteza ; Namiranian, Khodadad ; Hajrasouliha, Amir R. ; Tavakoli, Sina ; Ebrahimi, Farzad ; Dehpour, Ahmad Raza. / α2-adrenoceptor subsensitivity in mesenteric vascular bed of cholestatic rats : The role of nitric oxide and endogenous opioids. In: European Journal of Pharmacology. 2005 ; Vol. 514, No. 2-3. pp. 183-189.
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T2 - The role of nitric oxide and endogenous opioids

AU - Borhani, Amir Ali

AU - Houshmand, Golbahar

AU - Samini, Morteza

AU - Namiranian, Khodadad

AU - Hajrasouliha, Amir R.

AU - Tavakoli, Sina

AU - Ebrahimi, Farzad

AU - Dehpour, Ahmad Raza

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N2 - 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 α2-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 α2- 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 α2-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 < 0.01) and the dose of clonidine that causes 50% of maximum response (ED 50) was significantly higher in cholestatic rats (P < 0.05). Vasodilation response to sodium nitroprusside was the same in cholestatic and sham-operated rats. Seven-day treatment with aminoguanidine recovered the effect of cholestasis. Seven-day treatment with naltrexone caused an increase in maximum response (P < 0.01) and a decrease in ED50 (P < 0.05) in cholestatic rats, while this treatment in sham-operated rats caused a decrease in the maximum response (P < 0.01) and an increase in ED 50 (P < 0.05). This study showed that cholestasis is associated with decreased responsiveness of mesenteric vascular bed to clonidine and the cholestasis-associated NO overproduction and increased level of endogenous opioids may contribute to this process.

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KW - Cholestasis

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KW - Mesenteric vascular bed

KW - Nitric oxide

KW - Opioid

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