Potentiation of anandamide effects in mesenteric beds isolated from bile duct-ligated rats: role of nitric oxide.
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 nitric oxide (NO) overproduction. On the other hand, it is well known that anandamide, an endogenous cannabinoid ligand, causes hypotension and a decrease in systemic vascular resistance. In the present study, the possible role of the cannabinoid system in cholestasis-induced mesenteric vascular bed responsiveness was investigated. Mesenteric arteries of bile duct-ligated and sham-operated rats receiving daily administrations of saline were used for evaluating phenylephrine or anandamide dose-response, acute effects of N(G)-nitro-L-arginine methyl ester (L-NAME, 100 microM), a non-selective inhibitor of NO synthase (NOS), or naltrexone, an opioid receptors antagonist (1 microM). The other groups of bile duct-ligated and sham-operated rats received daily intraperitoneal administration of L-NAME (20 mg/kg/day), aminoguanidine, a selective inducible NOS (iNOS) inhibitor (150 mg/kg/day) or naltrexone (10 mg/kg/day). After 7 days, the superior mesenteric artery was cannulated and the mesenteric vascular bed was perfused according to the McGregor method. Anandamide-induced relaxation was significantly potentiated in mesenteric vascular beds of bile duct-ligated rats. Chronic treatment of bile duct-ligated animals with L-NAME and aminoguanidine blocked this hyperresponsiveness while the hyperresponsiveness was potentiated at large doses of anandamide on chronic treatment of these animals with naltrexone. Although acute L-NAME treatment of mesenteric beds completely blocked the anandamide-induced vasorelaxation in sham-operated rats, this vasorelaxation still was present in bile duct-ligated animals. Anandamide-induced vasorelaxation remained unaffected after acute naltrexone treatment of mesenteric beds in both bile duct-ligated and sham-operated rats. Our results indicate that (1) there is enhanced anandamide-induced vasorelaxation in cholestatic rats, probably due to a defect in cannabinoid or vanilloid receptors and (2) NO overproduction may be involved in cholestasis-induced vascular hyperresponsiveness.
Moezi
Leila
L
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O.Box 13145-784, Tehran, Iran.
Rezayat
Mehdi
M
Samini
Morteza
M
Shafaroodi
Hamed
H
Mehr
Shahram Ejtemaie
SE
Ebrahimkhani
Mohammad R
MR
Dehpour
Ahmad R
AR
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D001652:Bile Ducts / Q000187:drug effects* / Q000502:physiology / Q000601:surgery; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D063388:Endocannabinoids; D066298:In Vitro Techniques; D008026:Ligation; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000502:physiology; D009569:Nitric Oxide / Q000502:physiology*; D053284:Polyunsaturated Alkamides; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D001095:Arachidonic Acids; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D009569:Nitric Oxide; C078814:anandamide