Abstract
There is large interindividual variability and ethnic differences in phenylephrine-mediated vasoconstriction. We tested the hypothesis that genetic variation in ADRA1A, the α1A adrenergic receptor gene, contributes to the variability and ethnic differences. We measured local dorsal hand vein responses to increasing doses of phenylephrine in 64 Caucasians and 42 African-Americans and genotyped for 32 ADRA1A single nucleotide polymorphisms. The ED50 ranged from 11 to 5442 ng min−1, and the Emax ranged from 13.5–100%. The rs574647 variant was associated with a trend towards lower logED50 in each race and in the combined cohort (P=0.008). In addition, rs1079078 was associated with a trend to higher logED50 in each race and in the combined cohort (P=0.011). Neither variant accounted for the ethnic differences in response. None of the ADRA1A haplotypes was associated with the outcomes. In conclusion, ADRA1A variants do not contribute substantially to the marked interindividual variability or ethnic differences in phenylephrine-mediated venoconstriction.
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References
Docherty JR . Subtypes of functional alpha1-adrenoceptor. Cell Mol Life Sci 2010; 67: 405–417.
Tanoue A, Koshimizu TA, Tsujimoto G . Transgenic studies of alpha(1)-adrenergic receptor subtype function. Life Sci 2002; 71: 2207–2215.
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.
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.
Muszkat M, Sofowora GG, Wood AJ, Stein CM . Alpha2-adrenergic receptor-induced vascular constriction in blacks and whites. Hypertension 2004; 43: 31–35.
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.
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.
Johnson JA, Liggett SB . Cardiovascular pharmacogenomics of adrenergic receptor signaling: clinical implications and future directions. Clin Pharmacol Ther 2011; 89: 366–378.
Klabunde RE . Cardiovascular physiology concepts: Vascular smooth muscle contraction and relaxation. http://www.cvphysiology.com/BloodPressure/BP026.htm; Last accessed on 08/08/2014.
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.
Posti JP, Valve L, Ruohonen S, Akkila J, Scheinin M, Snapir A . Dorsal hand vein responses to the alpha-adrenoceptor agonist phenylephrine do not predict responses to the alpha-adrenoceptor agonist dexmedetomidine. Eur J Pharmacol 2011; 653: 70–74.
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.
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.
Schindler C, Grossmann M, Dobrev D, Francke K, Ravens U, Kirch W . Reproducibility of dorsal hand vein responses to phenylephrine and prostaglandin F2 alpha using the dorsal hand vein compliance method. J Clin Pharmacol 2003; 43: 228–236.
Alradi AO, Carruthers SG . Evaluation and application of the linear variable differential transformer technique for the assessment of human dorsal hand vein alpha-receptor activity. Clin Pharmacol Ther 1985; 38: 495–502.
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.
Livak KJ . SNP genotyping by the 5'-nuclease reaction. Methods Mol Biol 2003; 212: 129–147.
Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA . Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet 2002; 70: 425–434.
Sinnwell JP, Schaid DJ haplo.stats: Statistical Analysis of Haplotypes with Traits and Covariates when Linkage Phase is Ambiguous. v 1.6.8 http://cran.rproject.org/web/packages/haplo.stats/index.html.
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.
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.
Xie HG, Kim RB, Stein CM, Gainer JV, Brown NJ, Wood AJ . Alpha1A-adrenergic receptor polymorphism: association with ethnicity but not essential hypertension. Pharmacogenetics 1999; 9: 651–656.
Freitas SR, Pereira AC, Floriano MS, Mill JG, Krieger JE . Association of alpha1a-adrenergic receptor polymorphism and blood pressure phenotypes in the Brazilian population. BMC Cardiovasc Disord 2008; 8: 40.
Gu D, Su S, Ge D, Chen S, Huang J, Li B et al. Association study with 33 single-nucleotide polymorphisms in 11 candidate genes for hypertension in Chinese. Hypertension 2006; 47: 1147–1154.
Gu D, Ge D, Snieder H, He J, Chen S, Huang J et al. Association of alpha1A adrenergic receptor gene variants on chromosome 8p21 with human stage 2 hypertension. J Hypertens 2006; 24: 1049–1056.
Iacoviello M, Forleo C, Sorrentino S, Romito R, De TE, Lucarelli K et al. Alpha- and beta-adrenergic receptor polymorphisms in hypertensive and normotensive offspring. J Cardiovasc Med (Hagerstown) 2006; 7: 316–321.
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.
Franceschini N, Fox E, Zhang Z, Edwards TL, Nalls MA, Sung YJ et al. Genome-wide association analysis of blood-pressure traits in African-ancestry individuals reveals common associated genes in African and non-African populations. Am J Hum Genet 2013; 93: 545–554.
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.
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.
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. 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 α1A-adrenergic receptor and phenylephrine-mediated venoconstriction. Pharmacogenomics J 15, 310–315 (2015). https://doi.org/10.1038/tpj.2014.69
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DOI: https://doi.org/10.1038/tpj.2014.69
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