title: Clonidine induced endothelium-dependent tonic contraction in circular muscle of the rat hepatic portal vein.
abstract: Clonidine, an alpha2-agonist, has been shown to be useful in the treatment of hepatic portal hypertension in cirrhosis. The mechanism has been attributed to a clonidine-induced decrease in sympathetic activity. While clonidine has been shown to stimulate the alpha2-adrenoceptors of blood vessels, there is limited knowledge of the effects of clonidine on the circular muscle of the hepatic portal vein which regulates its blood flow. To investigate clonidine-induced contraction of the circular muscle of the hepatic portal vein and to clarify the possible role of the endothelium in the contraction, we examined the effects of clonidine on the isometric contraction of endothelium-intact and -removed ring preparations of the rat hepatic portal vein. In endothelium-intact preparations, clonidine caused a concentration-dependent increase in the amplitude of contractions. Inhibition of NO synthesis with Nomega-nitro-L-arginine (L-NNA) elevated the resting tone, and increased the amplitude of the clonidine-induced contractions. Inhibition of cyclooxygenase by diclofenac did not change the amplitude of the clonidine-induced contractions observed both in the presence and absence of L-NNA. Application of a single concentration of clonidine induced a clear increase in amplitude of both twitch and tonic contractions. Twitch and tonic contractions induced by clonidine were inhibited by yohimbine. When the endothelium was damaged by sodium deoxycholate, tonic contractions induced by clonidine were completely suppressed, whereas the increase in twitch contractions was not influenced by chemical damage of the endothelium. Neither SKF-96365, a nonselective cation channel blocker, nor superoxide dismutase, a free radical scavenger, in the presence of catalase, changed the tonic contraction induced by clonidine. These results indicate that stimulation of alpha2-adrenoceptors enhanced twitch contractions and induced tonic contractions in the circular muscle of the rat hepatic portal vein, especially in the absence of NO. The latter, but not the former, occurs through an endothelium-dependent pathway.
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, 1757 Kanazawa, Ishikari-Tobetsu, Hokkaido 061-0293, Japan. shimamu@hoku-iryo-u.ac.jp
authors.forename: Keiichi
authors.initials: K
authors.lastname: Shimamura
authors.forename: Miyuki
authors.initials: M
authors.lastname: Toba
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kimura
authors.forename: Atsuko
authors.initials: A
authors.lastname: Ohashi
authors.forename: Kenji
authors.initials: K
authors.lastname: Kitamura
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D003000:Clonidine / Q000494:pharmacology*; D004008:Diclofenac / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006975:Hypertension, Portal / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D008103:Liver Cirrhosis / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology*; D009569:Nitric Oxide / Q000096:biosynthesis; D019335:Nitroarginine / Q000494:pharmacology; D011169:Portal Vein / Q000187:drug effects* / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000316:Adrenergic alpha-Agonists; D004008:Diclofenac; D019335:Nitroarginine; D009569:Nitric Oxide; D003000:Clonidine