title: Mesenteric vascular bed responsiveness in bile duct-ligated rats: roles of opioid and nitric oxide systems.
abstract: Changes in vascular responsiveness are proposed as the basis for some of the cardiovascular complications in cholestasis. Cholestasis is also associated with accumulation of endogenous opioid peptides and evidence of overproduction of nitric oxide (NO). The possible role of NO or opioid system in cholestasis-induced mesenteric vascular bed responsiveness was investigated. Bile duct-ligated and sham-operated rats were treated for 6 days with either normal saline, naltrexone, an opioid antagonist (20 mg/kg/day) or L-NAME (N(omega)-nitro-L-arginine methyl ester), a nitric oxide synthase inhibitor (3 mg/kg/day). After 7 days, the superior mesenteric artery was cannulated and the mesenteric vascular bed was perfused according to the McGregor method. Baseline perfusion pressure of the mesenteric vascular bed was decreased in bile duct-ligated compared to sham-operated animals. ED(50) of phenylephrine-induced vasoconstriction was increased, but vasoconstriction R(max) was not different in the vascular bed of bile duct-ligated rats and of sham-operated ones. Acetylcholine-induced vasorelaxation was impaired in bile duct-ligated rats (increased ED(50) and decreased vasorelaxation R(max)). Sodium nitroprusside-induced vasorelaxation was not different between bile duct-ligated and sham-operated rats, implying that the smooth muscle components of vasorelaxation were intact. Chronic treatment with L-NAME partially restored both the acetylcholine-induced vasorelaxation and phenylephrine-induced vasoconstriction response in bile duct-ligated rats. Naltrexone treatment also partially restored the acetylcholine-induced vasorelaxation and phenylephrine-induced vasoconstriction in bile duct-ligated rats. There is impaired acetylcholine-induced vasorelaxation in cholestatic rats, probably due to a defect in endothelial function. This study also provided evidence for the involvement of increased opioidergic tone and NO overproduction in cholestasis-induced vascular hyporesponsiveness.
authors.affiliation: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O.Box 13145-784, Tehran, Iran.
authors.forename: K
authors.initials: K
authors.lastname: Namiranian
authors.forename: M
authors.initials: M
authors.lastname: Samini
authors.forename: S E
authors.initials: SE
authors.lastname: Mehr
authors.forename: S A
authors.initials: SA
authors.lastname: Gaskari
authors.forename: H
authors.initials: H
authors.lastname: Rastegar
authors.forename: H
authors.initials: H
authors.lastname: Homayoun
authors.forename: A R
authors.initials: AR
authors.lastname: Dehpour
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001652:Bile Ducts / Q000503:physiopathology* / Q000601:surgery; D002779:Cholestasis / Q000209:etiology / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008026:Ligation / Q000009:adverse effects; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000503:physiopathology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009599:Nitroprusside / Q000494:pharmacology; D018847:Opioid Peptides / Q000502:physiology; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009599:Nitroprusside; D010656:Phenylephrine; D009569:Nitric Oxide; D009271:Naltrexone; D019001:Nitric Oxide Synthase; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester