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 ␣ 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-9␣,11␣-methanoepoxy prostaglandin F 2␣ (U46619) in the presence or absence of indomethacin; N L-657,743, (2S-trans)-1,3,4,5Ј,6,6Ј,7,12b-octahydro-1Ј,3Ј-dimethyl-spiro[2H-benzofuro[2,3-a]quinolizine-2,4Ј(1ЈH)-pyrimidin]-2Ј(3ЈH)-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 (Ͼ30 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 ␣ 2A/D -adrenoceptors and possibly ␣ 2B -adrenoceptors. The contraction was mediated mainly by ␣ 2B -and ␣ 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.

Dexmedetomidine protects the heart against ischemia-reperfusion injury by an endothelial eNOS/NO dependent mechanism

“…Gi-protein, mediated by alpha2A-adrenergic receptors, and contraction was mediated by alpha2B and alpha1-adrenergic receptors and involved the action of prostanoids [67]. Furthermore, Porter et al showed that Dex increased actin cytoskeleton organization and inhibited isoproterenol-stimulated cAMP accumulation in the fetal rat heart.…”

Quantitative determination of α2B-adrenoceptor-evoked myosin light chain phosphorylation in vascular smooth muscle cells

“…Most studies on α 2 -adrenoceptor-mediated vascular smooth muscle contraction have employed isometric tension measurements on blood vessels, and the results have varied greatly depending on the luminal diameter of the vessel and its anatomical origin, with α 2 -adrenoceptors being more prominent in small arteries and veins but not in large arteries such as the aorta (Nielsen et al, 1989;Parkinson & Hughes, 1995;Roberts, 2001Roberts, , 2003. In particular, the vascular responses relating to dexmedetomidine appear to be very complex; in endotheliumdenuded arteries, the drug has induced contraction, whereas in intact vessels the relaxing and contracting effects of dexmedetomidine appear to oppose each other (Kim et al, 2009;Wong, Man, Vanhoutte, & Ng, 2010). In addition, dexmedetomidine has induced endotheliumdependent relaxation at low concentrations in contracted small arteries and contraction at higher concentrations (Wong et al, 2010).…”

“…In particular, the vascular responses relating to dexmedetomidine appear to be very complex; in endotheliumdenuded arteries, the drug has induced contraction, whereas in intact vessels the relaxing and contracting effects of dexmedetomidine appear to oppose each other (Kim et al, 2009;Wong, Man, Vanhoutte, & Ng, 2010). In addition, dexmedetomidine has induced endotheliumdependent relaxation at low concentrations in contracted small arteries and contraction at higher concentrations (Wong et al, 2010). Studies on cultured vascular smooth muscle cells have been focused on the monitoring of intracellular calcium levels (Chotani et al, 2004;Hughes, Parkinson, & Wijetunge, 1996;Mironneau & Macrez-Lepretre, 1995).…”

Effect of Dexmedetomidine on Dose Requirement of Propofol and Thiopentone Induction in Patients Under General Endotracheal Anesthesia

“…Dexmedetomidine has α2:α1 binding selectivity ratio of 1620:1 compared to 220:1 for clonidine [5], and more predictable pharmacokinetic properties compared to clonidine [9,10]. It also possesses selective α2-adrenoceptor agonism, especially for the 2A subtype of this receptor, which causes it to be a much more effective sedative and analgesic agent than clonidine [11,12].…”