Dexmedetomidine induces both relaxations and contractions, via different α2-adrenoceptor subtypes, in the isolated mesenteric artery and aorta of the rat

Abstract

Dexmedetomidine is an α2-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 F2α (U46619) in the presence or absence of indomethacin; Nω-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 Gi protein, and it was mediated by α2A/D-adrenoceptors and possibly α2B- adrenoceptors. The contraction was mediated mainly by α2B- and α1-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. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics.