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J Hypertens. 2010 Feb;28(2):278-84. doi: 10.1097/HJH.0b013e328333d212.

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

Author information

  • 1Department of Medicine and Pharmacology, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-6602, USA.

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.

PMID:
20051907
[PubMed - indexed for MEDLINE]
PMCID:
PMC2895551
Free PMC Article

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