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Background and Objectives: Activation of α2-adrenergic receptors regulates a broad spectrum of physiologic responses, including blood pressure (centrally and peripherally), sedation, analgesia, insulin release, renal function, cognition, and behavior. The purpose of this study was to explore systematically the local vascular responses in humans triggered by a highly selective α2-adrenergic agonist (azepexole [B-HT 933]) and whether such responses are dose-dependent or influenced by age, gender, or allelic variation at the drug's receptor. Methods: We evaluated dorsal hand vein vascular responses to the infusion of a wide spectrum of doses of azepexole, assessing any venodilation, as well as the maximal extent of venoconstriction (Bmax) and the dose that produced a half-maximal effect (Kd), in 50 healthy normotensive adults of both genders and 4 ethnicities. Genomic deoxyribonucleic acid from the study subjects was evaluated at polymorphisms of the α2B-adrenergic receptor gene (ADRA2B). Results: We found previously unreported initial venodilation to low doses (10-100 ng/min) of azepexole, followed by progressive, intense venoconstriction to higher doses (200-100,000 ng/min) of the drug. Younger individuals (aged <30 years) had less venodilation than older individuals (aged >30 years) with low doses of azepexole but had a greater extent of venoconstriction at higher doses of azepexole (ANOVA, P = .001). Men had less venodilation than women with low doses of azepexole but greater venoconstriction with higher doses (ANOVA, P = .036). Several common polymorphisms (>10% minor allele frequency) at ADRA2B (insertion/deletion polymorphism [Glu322-325],G-98C, C1182A, and C1776A) did not show an association with either Bmax or Kd for the drug response. The A36G (Thr12Thr) synonymous single nucleotide polymorphism displayed a nonsignificant trend (P = .073) toward higher Kd in A/G heterozygotes compared with A/A homozygotes. Conclusions: Local infusion into the human dorsal hand vein of a highly selective α2-adrenergic agonist, azepexole, produces biphasic responses, with venodilation at a low dose and intense venoconstriction at a higher concentration. These responses to azepexole show prominent differences as a function of age and gender but appear not to depend on common allelic variations at the ADRA2B receptor. [ABSTRACT FROM AUTHOR]