Abstract
The alpha1B (α1B)-adrenergic receptors contribute to vasoconstriction in humans. We tested the hypothesis that variation in the ADRA1B gene contributes to interindividual variability and ethnic differences in adrenergic vasoconstriction. We measured dorsal hand vein responses to increasing doses of phenylephrine in 64 Caucasians and 41 African Americans and genotyped 34 ADRA1B variants. We validated findings in another model of catecholamine-induced vasoconstriction, the increase in mean arterial pressure (ΔMAP) during a cold pressor test (CPT). One ADRA1B variant, rs10070745, present in 14 African-American heterozygotes but not in Caucasians, was associated with a lower phenylephrine ED50 (geometric mean (95% confidence interval), 144 (69–299) ng ml−1) compared with 27 African-American non-carriers (208 (130–334) ng ml−1; P=0.015) and contributed to the ethnic differences in ED50. The same variant was also associated with a greater ΔMAP during CPT (P=0.008). In conclusion, ADRA1B rs10070745 was significantly associated with vasoconstrictor responses after adrenergic stimulation and contributed to the ethnic difference in phenylephrine sensitivity.
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References
Rudner XL, Berkowitz DE, Booth JV, Funk BL, Cozart KL, D'Amico EB et al. Subtype specific regulation of human vascular alpha(1)-adrenergic receptors by vessel bed and age. Circulation 1999; 100: 2336–2343.
Leech CJ, Faber JE . Different alpha-adrenoceptor subtypes mediate constriction of arterioles and venules. Am J Physiol 1996; 270: H710–H722.
Docherty JR . Subtypes of functional alpha1-adrenoceptor. Cell Mol Life Sci 2010; 67: 405–417.
Yan M, Sun J, Bird PI, Liu DL, Grigg M, Lim YL . Alpha1A- and alpha1B-adrenoceptors are the major subtypes in human saphenous vein. Life Sci 2001; 68: 1191–1198.
Adefurin A, Ghimire LV, Kohli U, Muszkat M, Sofowora GG, Paranjape SY et al. Blacks have a greater sensitivity to alpha1-adrenoceptor-mediated venoconstriction compared with Whites. Hypertension 2013; 61: 915–920.
Sofowora GG, Dishy V, Landau R, Xie HG, Prasad HC, Byrne DW et al. Alpha 1A-adrenergic receptor polymorphism and vascular response. Clin Pharmacol Ther 2004; 75: 539–545.
Adefurin A, Ghimire LV, Kohli U, Muszkat M, Sofowora GG, Li C et al. Genetic variation in the alpha-adrenergic receptor and phenylephrine-mediated venoconstriction. Pharmacogenomics J 2014; 15: 310–315.
Kelsey RM, Alpert BS, Dahmer MK, Krushkal J, Quasney MW . Alpha-adrenergic receptor gene polymorphisms and cardiovascular reactivity to stress in Black adolescents and young adults. Psychophysiology 2012; 49: 401–412.
Yang X, Gu D, He J, Hixson JE, Rao DC, Lu F et al. Genome-wide linkage and regional association study of blood pressure response to the cold pressor test in Han Chinese: the genetic epidemiology network of salt sensitivity study. Circ Cardiovasc Genet 2014; 7: 521–528.
He J, Kelly TN, Zhao Q, Li H, Huang J, Wang L et al. Genome-wide association study identifies 8 novel loci associated with blood pressure responses to interventions in Han Chinese. Circ Cardiovasc Genet 2013; 6: 598–607.
Reder NP, Tayo BO, Salako B, Ogunniyi A, Adeyemo A, Rotimi C et al. Adrenergic alpha-1 pathway is associated with hypertension among Nigerians in a pathway-focused analysis. PLoS One 2012; 7: e37145.
Cavalli A, Lattion AL, Hummler E, Nenniger M, Pedrazzini T, Aubert JF et al. Decreased blood pressure response in mice deficient of the alpha1b-adrenergic receptor. Proc Natl Acad Sci USA 1997; 94: 11589–11594.
Tanoue A, Koshimizu TA, Tsujimoto G . Transgenic studies of alpha(1)-adrenergic receptor subtype function. Life Sci 2002; 71: 2207–2215.
Smith KM, Macmillan JB, McGrath JC . Investigation of alpha1-adrenoceptor subtypes mediating vasoconstriction in rabbit cutaneous resistance arteries. Br J Pharmacol 1997; 122: 825–832.
Buscher R, Herrmann V, Ring KM, Kailasam MT, O'Connor DT, Parmer RJ et al. Variability in phenylephrine response and essential hypertension: a search for human alpha(1B)-adrenergic receptor polymorphisms. J Pharmacol Exp Ther 1999; 291: 793–798.
Buzas B, Belfer I, Hipp H, Lorincz I, Evans C, Phillips G et al. Haplotype block and superblock structures of the alpha1-adrenergic receptor genes reveal echoes from the chromosomal past. Mol Genet Genomics 2004; 272: 519–529.
Stein CM, Lang CC, Singh I, He HB, Wood AJ . Increased vascular adrenergic vasoconstriction and decreased vasodilation in blacks. Additive mechanisms leading to enhanced vascular reactivity. Hypertension 2000; 36: 945–951.
Kurnik D, Friedman EA, Muszkat M, Sofowora GG, Xie HG, Dupont WD et al. Genetic variants in the alpha2C-adrenoceptor and G-protein contribute to ethnic differences in cardiovascular stress responses. Pharmacogenet Genomics 2008; 18: 743–750.
Kohli U, Muszkat M, Sofowora GG, Harris PA, Friedman EA, Dupont WD et al. Effects of variation in the human alpha2A- and alpha2C-adrenoceptor genes on cognitive tasks and pain perception. Eur J Pain 2010; 14: 154–159.
He HB, Deegan RJ, Wood M, Wood AJ . Optimization of high-performance liquid chromatographic assay for catecholamines. Determination of optimal mobile phase composition and elimination of species-dependent differences in extraction recovery of 3,4-dihydroxybenzylamine. J Chromatogr 1992; 574: 213–218.
Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.
Muszkat M, Kurnik D, Sofowora GG, Wood AJ, Stein CM . Independent regulation of alpha1 and alpha2 adrenergic receptor-mediated vasoconstriction in vivo. J Hypertens 2011; 29: 251–256.
Purcell SNB, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, Maller J et al. PLINK: a toolset for whole-genome association and population-based linkage analysis. Am J Hum Genet 2007; 81: 559–575.
Sham PC, Purcell SM . Statistical power and significance testing in large-scale genetic studies. Nat Rev Genet 2014; 15: 335–346.
Giessler C, Wangemann T, Silber RE, Dhein S, Brodde OE . Noradrenaline-induced contraction of human saphenous vein and human internal mammary artery: involvement of different alpha-adrenoceptor subtypes. Naunyn Schmiedebergs Arch Pharmacol 2002; 366: 104–109.
Theroux TL, Esbenshade TA, Peavy RD, Minneman KP . Coupling efficiencies of human alpha 1-adrenergic receptor subtypes: titration of receptor density and responsiveness with inducible and repressible expression vectors. Mol Pharmacol 1996; 50: 1376–1387.
Hosoda C, Koshimizu TA, Tanoue A, Nasa Y, Oikawa R, Tomabechi T et al. Two alpha1-adrenergic receptor subtypes regulating the vasopressor response have differential roles in blood pressure regulation. Mol Pharmacol 2005; 67: 912–922.
Flordellis C, Paris H, Karabinis A, Lymperopoulos A . Pharmacogenomics of adrenoceptors. Pharmacogenomics 2004; 5: 803–817.
Krushkal J, Xiong M, Ferrell R, Sing CF, Turner ST, Boerwinkle E . Linkage and association of adrenergic and dopamine receptor genes in the distal portion of the long arm of chromosome 5 with systolic blood pressure variation. Hum Mol Genet 1998; 7: 1379–1383.
Gupta A, Carruthers SG . Familial studies of heritability of alpha1-adrenergic receptor responsiveness in superficial veins. Clin Pharmacol Ther 1997; 62: 322–326.
Luthra A, Borkowski KR, Carruthers SG . Genetic aspects of variability in superficial vein responsiveness to norepinephrine. Clin Pharmacol Ther 1991; 49: 355–361.
Muszkat M, Sofowora GG, Wood AJ, Stein CM . Alpha2-adrenergic receptor-induced vascular constriction in blacks and whites. Hypertension 2004; 43: 31–35.
Acknowledgements
This study was supported by Vanderbilt CTSA grant 1 UL1 TR000445 from the National Center for Research Resources and P01 HL56693 from the National Institutes of Health. The research of AA reported in this publication was supported by the National Institute of General Medical Science of the National Institutes of Health under award number T32 GM007569. CMS is the recipient of the Dan May Chair in Medicine.
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Adefurin, A., Ghimire, L., Kohli, U. et al. Genetic variation in the alpha1B-adrenergic receptor and vascular response. Pharmacogenomics J 17, 366–371 (2017). https://doi.org/10.1038/tpj.2016.29
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DOI: https://doi.org/10.1038/tpj.2016.29
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