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


CONCLUSIONS
Common ADRA2B variants contribute to the interindividual variability in vascular desensitization to an alpha2-AR agonist in vivo.
Muszkat
Mordechai
M
Department of Medicine and Pharmacology, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-6602, USA.
Kurnik
Daniel
D
Sofowora
Gbenga G
GG
Solus
Joseph
J
Xie
Hong-Guang
HG
Harris
Paul A
PA
Williams
Scott M
SM
Wood
Alastair J J
AJ
Stein
C Michael
CM
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000328:Adult; D001808:Blood Vessels / Q000187:drug effects; D020927:Dexmedetomidine / Q000494:pharmacology*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D010597:Pharmacogenetics; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics*; D017384:Sequence Deletion; D014661:Vasoconstriction / Q000187:drug effects* / Q000235:genetics*; D055815:Young Adult
C547771:ADRA2B protein, human; D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D018341:Receptors, Adrenergic, alpha-2; D020927:Dexmedetomidine