title: Alpha2B adrenergic receptor 301-303 deletion polymorphism and vascular alpha2 adrenergic receptor response.
abstract: Postsynaptic alpha2B adrenergic receptors (ARs) mediate vasoconstriction. There is more than 1000-fold variability in vascular sensitivity to an alpha2-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 alpha2B-AR gene and has functional effects in vitro. Thus, we examined the hypothesis that the del301-303 polymorphism contributes to variability in vascular alpha2-AR responses in vivo. Healthy subjects were recruited based on their alpha2B-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 alpha2-AR agonist, dexmedetomidine, into a dorsal hand vein. The dose that produced 50% (ED50) of maximum venoconstriction (Emax) 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 ED50 and Emax among the alpha2B-AR del301-303 genotypes. The ED50 was 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 Emax was 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 alpha2-AR activation in the hand vein.
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6602, USA.
authors.forename: Mordechai
authors.initials: M
authors.lastname: Muszkat
authors.forename: Gbenga G
authors.initials: GG
authors.lastname: Sofowora
authors.forename: Hong-Guang
authors.initials: HG
authors.lastname: Xie
authors.forename: Alastair J J
authors.initials: AJ
authors.lastname: Wood
authors.forename: C Michael
authors.initials: CM
authors.lastname: Stein
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000328:Adult; D020927:Dexmedetomidine / Q000494:pharmacology; D005260:Female; D017353:Gene Deletion; D014644:Genetic Variation; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008297:Male; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics*; D014680:Veins / Q000187:drug effects
chemical_list: C547771:ADRA2B protein, human; D000316:Adrenergic alpha-Agonists; D018341:Receptors, Adrenergic, alpha-2; D020927:Dexmedetomidine