OIII-B-3Variation in the α2B adrenergic receptor and its relationship to desensitization of vascular response to agonist in vivo

Abstract

AIMS Vascular α2B adrenergic receptor (ADRA2B) mediate vasoconstriction and contribute to peripheral regulation of vascular tone. In vitro, ADRA2B undergoes agonist-induced desensitization and a common genetic variation, 301–303 deletion, was associated with loss of desensitization. We previously characterized variation in ADRA2B and observed 24 variant sites. This study examines the hypothesis that the 301–303del or other variants alter vascular desensitization in response to the selective ADRA2 agonist, dexmedetomidine (D) in vivo. METHODS Venoconstriction in response to D (0.01–1000 ng/min) was measured in the dorsal hand vein using a linear variable differential transformer in 40 healthy subjects (age 18–45 yrs). On a separate day, the dose that had caused > 50% constriction in the dose-response study was infused for 180 min and response measured. The area under the curve for response, normalized to the initial response (nAUC) was calculated. 5812 bp of contiguous sequence of ADRA2B were examined by bidirectional sequencing, and relationship of ADRA2B variants to nAUC determined. RESULTS Six variants (1 promoter, 3 coding, 2 3′ UTR) were found with an allele frequency> 5%. nAUC was 0.93 ± 0.22 (mean±SD). 301–303del or other common variant did not contribute to variability in nAUC.[Ins/Ins (n=22): 0.89 ± 0.23, Ins/del (n=11): 0.98 ±0.24, del/del (n=7): 0.98 ±0.16; pANOVA= 0.47]. CONCLUSION Common variants in ADRA2B do not contribute substantially to ADRA2B vascular desensitization in vivo. Clinical Pharmacology & Therapeutics (2005) 79, P31–P31; doi: 10.1016/j.clpt.2005.12.112