Dual alpha(2)-adrenergic agonist and alpha(1)-adrenergic antagonist actions of dexmedetomidine on human isolated endothelium-denuded gastroepiploic arteries.
The actions of dexmedetomidine (DEX) on human vascular smooth muscle are unclear. We investigated its effects on isolated, endothelium-denuded human gastroepiploic arteries in vitro and compared them with clonidine (CLO). DEX had little direct effect on resting tension, whereas CLO produced small contractile responses, an effect which is blocked by the alpha(1)-adrenergic antagonist prazosin. DEX markedly enhanced the high K(+) (40 mmol/L)-induced contraction, and this effect was reversed by the alpha(2)-adrenergic antagonists yohimbine and rauwolscine but unaffected by prazosin. However, CLO had little effect on the K(+) contractions. Interestingly, larger concentrations (>10(-7) mol/L) of both alpha(2)-adrenergic stimulants significantly inhibited the contractions elicited by the alpha(1)-adrenergic agonist phenylephrine (10(-6) mol/L) and, to a lesser extent, those elicited by the alpha(1)/alpha(2)-agonist norepinephrine (10(-6) mol/L). These results suggest the possibility that DEX and CLO each have a high affinity for alpha(1)-adrenoceptors in human isolated gastroepiploic arteries, resulting in a reduced efficacy of alpha(1)-adrenergic activation by alpha-agonists. The differing affinities of the drugs for alpha(1)- and alpha(2)-adrenoceptors may help explain their additional actions: 1) DEX enhances the high K(+)-induced contraction presumably through alpha(2)-adrenoceptor activation, and 2) CLO acts on alpha(1)-adrenoceptors as a partial agonist when present alone.


CONCLUSIONS
Dexmedetomidine may not directly affect smooth muscle in human peripheral resistance vessels within the usual range of plasma concentrations (<10(-7) mol/L) achieved in clinical practice. However, in large doses, it could enhance the response to nonadrenergic vasoconstrictor agonists while antagonizing the vasoconstrictor response to alpha(1)-adrenoceptor agonists.
Hamasaki
Junichirou
J
Department of Anesthesiology and Critical Care Medicine, Kagoshima University School of Medicine, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan. hamasak1@m2.kufm.kagoshima-u.ac.jp
Tsuneyoshi
Isao
I
Katai
Rumi
R
Hidaka
Tatewaki
T
Boyle
Walter A
WA
Kanmura
Yuichi
Y
D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D001158:Arteries / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology; D020927:Dexmedetomidine / Q000494:pharmacology*; D004347:Drug Interactions; D004730:Endothelium, Vascular / Q000502:physiology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011188:Potassium / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D013270:Stomach / Q000098:blood supply
D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D020927:Dexmedetomidine; D003000:Clonidine; D011188:Potassium