Dataset Information

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.

SUBMITTER: Muszkat M

PROVIDER: S-EPMC2895551 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Publications

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

Muszkat Mordechai M 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

Journal of hypertension 20100201 2

<h4>Objectives</h4>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.<h4>Methods</h4>We measured sensitivity to a highly selective alpha2-AR agonist, dexmedetomidine, (0.01-1000 n ...[more]

PMID: 20051907

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Project description:BackgroundCatecholamines govern stress blood pressure responses. Catecholaminergic responses may be partially genetic and contribute to the complex heritability of hypertension.Methods and resultsTo evaluate catecholaminergic responses without systemic counterregulation, we infused graded concentrations of tyramine, an indirect presynaptic norepinephrine releaser, into dorsal hand veins of 49 normotensive men and women of 5 ethnicities. Vascular responses were coupled to common (minor allele frequency >10%) single-nucleotide polymorphisms at adrenergic target loci within presynaptic pathways. Significance was set at P<0.003 after Bonferroni correction. Generalized analysis of molecular variance (GAMOVA) was performed to determine whether genetic admixture contributed to results. Venoconstriction progressed to 47% with increasing concentrations of tyramine (0.129 to 25.8 mmol/L; P<0.001). Family history of hypertension (P<0.001) and female sex (P=0.02) predicted blunted tyramine responses. Two genetic loci significantly predicted vascular response: chromogranin B, which encodes a protein that catalyzes catecholamine vesicle formation (CHGB, exon 4, Glu348Glu; P=0.002), and cytochrome b-561 (CYB561, intron 1, C719G; P<0.001), an electron shuttle for catecholamine synthesis. Stepwise regression suggested important effects for the CHGB locus, with polymorphisms for the vacuolar-ATPase beta-subunit (ATP6V1B1, exon 1, Ile30Thr) and flavin-containing monooxygenase-3 (FMO3, exon 3, Lys158Glu, P=0.002). GAMOVA did not show a significant relationship between overall genetic profile and hand-vein constriction (P=0.29), which indicates that population stratification did not contribute to this phenotype.ConclusionsLocally infused tyramine produced dose-dependent pressor responses, predicted by family history of hypertension, sex, and genetic variants at loci, particularly CHGB, that encode the biosynthesis, storage, and metabolism of catecholamines. Such variants may influence the complex heritability of adrenergic responses and perhaps hypertension.

Dataset Information

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

Objectives

Methods

Results

Conclusion

Publications

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

Similar Datasets

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