Dexmedetomidine induces both relaxations and contractions, via different {alpha}2-adrenoceptor subtypes, in the isolated mesenteric artery and aorta of the rat.
Dexmedetomidine is an α(2)-adrenoceptor agonist and anesthetic. The present study was designed to characterize the receptor subtypes and the downstream mechanisms of the vascular effects of dexmedetomidine in small (mesenteric artery) and large (aorta) arteries ex vivo. Isometric tension was measured in Sprague-Dawley rat mesenteric and aortic rings (with or without endothelium). To study relaxations, cumulative concentrations of dexmedetomidine, 5-bromo-N-(2-imidazolin-2-yl)-6-quinoxalinamine, (UK14304), or clonidine were added to rings contracted with 9,11-dideoxy-9α,11α-methanoepoxy prostaglandin F(2α) (U46619) in the presence or absence of indomethacin; N(ω)-nitro-l-arginine methyl ester hydrochloride (l-NAME); 2-[2H-(1-methyl-1,3-dihydroisoindole)methyl]-4,5-dihydroimidazole maleate (BRL44408); 2-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]-4,4-dimethyl-1,3-(2H,4H)-isoquinolindione dihydrochloride (ARC239); l-657,743, (2S-trans)-1,3,4,5',6,6',7,12b-octahydro-1',3'-dimethyl-spiro[2H-benzofuro[2,3-a]quinolizine-2,4'(1'H)-pyrimidin]-2'(3'H)-one hydrochloride hydrate (MK912); rauwolscine; prazosin; or pertussis toxin. To study contractions, dexmedetomidine was added to quiescent rings without endothelium or after incubation with l-NAME, rauwolscine, prazosin, indomethacin, or 3-[(6-amino-(4-chlorobenzensulfonyl)-2-methyl-5,6,7,8-tetrahydronaphth)-1-yl]propionic acid (S18886). Dexmedetomidine evoked relaxation at low concentrations (10 pM-30 nM) followed by contraction at higher concentrations (>30 nM) in the mesenteric artery. In the aorta, the relaxation was significantly smaller. The relaxation to dexmedetomidine depended on nitric oxide, endothelium, and G(i) protein, and it was mediated by α(2A/D)-adrenoceptors and possibly α(2B)-adrenoceptors. The contraction was mediated mainly by α(2B)- and α(1)-adrenoceptors and involved the action of prostanoids. UK14304 and clonidine induced greater and smaller relaxations, respectively, than dexmedetomidine. In conclusion, depending on the concentration used and the presence of functional endothelium, dexmedetomidine may evoke both relaxation and contraction in isolated arteries. The vascular effects also vary depending on the blood vessel studied. Its vascular effect is different from that of clonidine and UK14304.
Wong
Emily S W
ES
Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, HKSAR, China.
Man
Ricky Y K
RY
Vanhoutte
Paul M
PM
Ng
Kwok F J
KF
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology; D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects*; D000068438:Brimonidine Tartrate; D003000:Clonidine / Q000494:pharmacology; D020927:Dexmedetomidine / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects*; D008954:Models, Biological; D009119:Muscle Contraction / Q000187:drug effects*; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D037342:Pertussis Toxin / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors
D058668:Adrenergic alpha-1 Receptor Antagonists; D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D009281:Naphthalenes; D011422:Propionates; D011810:Quinoxalines; D018341:Receptors, Adrenergic, alpha-2; D017482:Receptors, Thromboxane; D000068438:Brimonidine Tartrate; D020927:Dexmedetomidine; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C501362:terutroban; D037342:Pertussis Toxin; D003000:Clonidine; D019331:NG-Nitroarginine Methyl Ester; D011224:Prazosin; D007213:Indomethacin