Desensitization of vascular response in vivo: contribution of genetic variation in the [alpha]2B-adrenergic receptor subtype

Abstract

Objectives: Vascular alpha2B-adrenergic receptors (alpha2B-ARs) mediate vasoconstriction and contribute to peripheral regulation of vascular tone. In vitro, a common 301-303 deletion in the alpha2B-AR gene, ADRA2B, results in loss of alpha2B-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 alpha2-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 alpha2-AR agonist in vivo.

Figure 1

Representative individual dorsal hand vein responses to 3 hour infusion of dexmedetomidine. The dotted line represents the theoretical response of no desensitization i.e., nAUC=1.0. Figure 1A shows an individual with stable venoconstriction and almost no desensitization (nAUC=0.98). Figure 1B shows an individual with decreased venoconstriction in response to the same dose of dexmedetomidine over time (i.e., desensitization). Negative constriction indicates venodilation beyond baseline (nAUC=0.44).

Figure 2

nAUC of dorsal hand vein responses to 3 hour infusion of dexmedetomidine according to ADRA2B del301-303 genotype [wt/wt (n=23), wt/del (n=11), del/del (n=7) subjects. The horizontal line and bars represent median and IQR. The dotted horizontal line represents no desensitization.