Desensitization of vascular response in vivo: Contribution of genetic variation in the α_2B-adrenergic receptor subtype

Objectives: Vascular αα_2B-adrenergic receptors (αα_2B-ARs) mediate vasoconstriction and contribute to peripheral regulation of vascular tone. In vitro, a common 301-303 deletion in the αα_2B-AR gene, ADRA2B, results in loss of αα_2B-AR desensitization. We examined the hypothesis that ADRA2B del301-303 or other common ADRA2B variants alter vascular desensitization in vivo. Methods: We measured sensitivity to a highly selective α2-AR agonist, dexmedetomidine, (0.01-1000 ng/min) in the dorsal hand vein in 41 healthy individuals. To induce desensitization a dose of dexmedetomidine that resulted in submaximal constriction was infused for 180 min and dorsal hand vein responses measured. Desensitization was defined as the ratio between the area-under-the-effect curve for each individual's response and the hypothetical area-under-the-effect curve assuming that the initial response had been maintained for 180 min (ratio below 1 reflecting desensitization). The relationship between six ADRA2B variants (one promoter, three coding, and two in the 3 untranslated region) with an allele frequency of more than 5% and desensitization was determined. Results: Forty-one individuals (22 men, 21 whites, age 18-45 years) were studied. The ADRA2B 301-303 deletion allele (ins/del and del/del, n = 18) was associated with resistance to desensitization [1.01 (interquartile range 0.90-1.06)] as compared with ins/ins homozygous individuals (n = 23) [0.91 (interquartile range 0.73-0.99)], P = 0.026. In addition, the-98 GG, 1182 CC, and 1776 CC genotypes were associated with significantly less desensitization than GC or CC, and CA or AA genotypes, respectively. Conclusion: Common ADRA2B variants contribute to the interindividual variability in vascular desensitization to an α2-AR agonist in vivo.