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 α1-adrenergic antagonist prazosin. DEX markedly enhanced the high K+ (40 mmol/L)-induced contraction, and this effect was reversed by the α2-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 α2-adrenergic stimulants significantly inhibited the contractions elicited by the α1-adrenergic agonist phenylephrine (10-6 mol/L) and, to a lesser extent, those elicited by the α1/α2-agonist norepinephrine (10-6 mol/L). These results suggest the possibility that DEX and CLO each have a high affinity for α1- adrenoceptors in human isolated gastroepiploic arteries, resulting in a reduced efficacy of α1-adrenergic activation by α-agonists. The differing affinities of the drugs for α1-and α2-adrenoceptors may help explain their additional actions: 1) DEX enhances the high K+-induced contraction presumably through α2-adrenoceptor activation, and 2) CLO acts on α1-adrenoceptors as a partial agonist when present alone.