α_2BAdrenergic receptor 301-303 deletion polymorphism and vascular α₂adrenergic receptor response

Postsynaptic α_2Badrenergic receptors (ARs) mediate vasoconstriction. There is more than 1000-fold variability in vascular sensitivity to an α₂-AR agonist. Genetic variability may contribute to such interindividual differences in sensitivity. A 301-303 deletion (del) polymorphism has been identified in the coding region of the α_2B-AR gene and has functional effects in vitro. Thus, we examined the hypothesis that the del301-303 polymorphism contributes to variability in vascular α₂-AR responses in vivo. Healthy subjects were recruited based on their α_2B-AR genotype. Their vascular sensitivity was determined using a linear variable differential transformer following the infusion of increasing doses (range 0.01-1000 ng/min) of the α₂-AR agonist, dexmedetomidine, into a dorsal hand vein. The dose that produced 50% (ED₅₀) of maximum venoconstriction (E_max) was determined for each subject. Vascular response was compared among the three genotypes. Forty-nine subjects were studied [28 wild-type wt/wt, 13 wt/del, 8 del/del]. There was no difference in dexmedetomidine ED₅₀and E_maxamong the α_2B-AR del301-303 genotypes. The ED₅₀was 1.39 ng/min [95% confidence interval (CI) 0.03-63.0 ng/min] in wt/wt subjects, 1.63 ng/min (95% CI 0.01-177.8 ng/min) in wt/del and 2.37 ng/min (95% CI 0.17-33.7 ng/min) in del/del (P =0.80). The average E_maxwas 75.4±14.9% in wt/wt, 75.7±21.3% in wt/del and 82.2±12.9% in del/del subjects (P =0.26). These findings suggest that the del301-303 polymorphism does not contribute significantly to interindividual in vivo variability in response to α₂-AR activation in the hand vein.