ORIGINAL ARTICLESα2B Adrenergic receptor 301–303 deletion polymorphism and vascular α2 adrenergic receptor responseMuszkat, Mordechai; Sofowora, Gbenga G.; Xie, Hong-Guang; Wood, Alastair J. J.; Michael Stein, C.Author Information Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA Sponsorship: The study was supported by United States Public Health Service grants HL56251, HL04012 and GM 5MO1-RR00095 and by the National Institutes of Health/National Institute of General Medical Sciences Pharmacogenetics Research Network and Database (U01GM61374, pharmgkb.org) under grant U01 HL65962. Dr M Muszkat was a recipient of a Merck Sharp & Dohme International Fellowship in Clinical Pharmacology. Correspondence and requests for reprints to C. Michael Stein, Division of Clinical Pharmacology, 560 PRB, Vanderbilt University School of Medicine, Nashville, TN 37232-6602, USA Tel: +1 615 936 3420; fax: +1 615 936 2746; e-mail: [email protected] Received 17 August 2004 Accepted 3 November 2004 Pharmacogenetics and Genomics: January 2005 - Volume 15 - Issue 1 - p 23-28 Buy Abstract Postsynaptic α2B adrenergic 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 α2B-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 α2B-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 (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 α2B-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 α2-AR activation in the hand vein. © 2005 Lippincott Williams & Wilkins, Inc.