Alpha-2B adrenergic receptor (ADRA2B) 301-303 deletion polymorphism and vascular desensitization in vivo

Abstract

Alpha-2 adrenergic receptors (ADRA2) play important roles in both central and peripheral regulation of vascular tone. The ADRA2B subtype mediates vasoconstriction and a common genetic variation, 301-303 deletion, was associated with loss of agonist-induced desensitization in vitro. Desensitization of vascular ADRA2 responses in vivo has not been previously described; nor is the effect of genetic variation known. We examined the hypothesis that 301-303del polymorphism affects vascular desensitization to the selective ADRA2 agonist, dexmedetomidine (Dex) in vivo. Incremental doses of Dex (0.01–1000 ng/min) were infused into a dorsal hand vein (DHV) in 28 healthy subjects (age 18-45 years) and responses measured using a linear variable differential transformer. A dose-response curve was constructed and the ED50 calculated. On a separate day, the Dex dose that had caused at least 50% venoconstriction in the dose-response study was infused for three hours and response measured every 30 minutes. The area under the curve for DHV response normalized to the initial response (nAUC) was calculated. Genotyping for 301-303del was performed, and relation to nAUC was determined. There was more than 3-fold inter-individual variability in nAUC. This was not related to ADRA2B genotype (p=0.846). Inter-individual variability in vascular responses to ADRA2 agonist over time occurs, but is not explained by the ADRA2B 301-303del. Clinical Pharmacology & Therapeutics (2004) 75, P95–P95; doi: 10.1016/j.clpt.2003.11.363