Objectives: The beta-2 adrenergic receptor is involved in mediating vasodilatation via neurohumoral and sympathetic nervous system pathways. Alterations in beta-2 adrenergic receptor gene expression (mRNA transcription) may contribute to the hypertensive phenotype. Human gene expression in clinical phenotypes remains largely unexplored due to ethical constraints involved in obtaining human tissue. We devised a method to obtain normally discarded internal mammary artery tissue from coronary artery bypass graft patients. We then investigated differences in hypertensive and normotensive participants' beta-2 adrenergic receptor gene expression in this tissue. Methods: We collected arterial tissue samples from 46 coronary artery bypass patients in a surgical setting. Using 41 of the samples, we performed TaqMan real-time polymerase chain reaction (RT-PCR) and used the delta delta cycle threshold (ΔΔCt) relative quantitation method for determination of fold-differences in gene expression between normotensive and hypertensive participants. The beta-2 adrenergic receptor target was normalized to glyceraldehyde-phosphate dehydrogenase. Results: Participants with hypertension had significantly less-expressed beta-2 adrenoceptor gene (2.76-fold, p < .05) compared to normotensive participants. After Bonferroni correction, gene expression did not differ by race, gender, type/dose of β-blocker prescribed, positive family history of hypertension, or diagnosis of diabetes mellitus type 2. Conclusions: These data support the possibility of a molecular basis for impaired adrenoceptor-mediated vascular tone in hypertension. Modification and extension of this research is required.
Anderson, N.B., McNeilly, M., & Myers, H. (1992). Toward understanding difference in autonomic reactivity: A proposed contextual model. In J. R. Turner (Ed.), Individual differences in cardiovascular response to stress. New York: Plenum Press , 125-145.
2.
Applied Biosystems (2008). Technical bulletin #178: RNase and DEPC treatment: Fact or laboratory myth. Retrieved March 3, 2008, from www.ambion.com/techlib/tb/tb_178.html.
3.
Bengtsson, K., Orho-Melander, M., Melander, O., Lindblad, U., Ranstam, J., Ranstam, L., et al. (2001). Beta(2)-adrenergic receptor gene variation and hypertension in subjects with type 2 diabetes. Hypertension , 37, 1303-1308.
4.
Brodde, O.E., Daul, A., & Michel, M.C. (1990). Subtypeselective modulation of human beta 1- and beta 2-adrenoceptor function by beta-adrenoceptor agonists and antagonists . Clinical Physiology and Biochemistry, 8 (Suppl. 2), 11-17.
5.
Brodde, O.E., Daul, A.E., O'Hara, N., Wang, X.L., & Bock, K.D. (1985). Acute regulation of lymphocyte beta 2-adrenoceptors is altered in patients with essential hypertension. Journal of Hypertension, 3, S129-S152.
6.
Bustin, S.A. (2002). Quantification of mRNA using real-time reverse transcription PCR (RT-PCR): Trends and problems. Journal of Molecular Endocrinology, 29, 23-39.
7.
Emilsson, V., Thorleifsson, G., Zhang, B., Leonardson, A.S., Zink, F., Zhu, J., et al. (2008). Genetics of gene expression and its effect on disease. Nature, 452, 423-428.
8.
Feldman, R.D. (2000). ß-adrenoceptor responsiveness in hypertension: Effects of dietary NaCl intake. British Journal of Pharmacology , 30, 55S-60S.
9.
Ferro, A., Kaumann, A.J., & Brown, M.J. (1993). Beta 1- and beta-2ADR-mediated relaxation in human internal mammary artery and saphenous vein: Unchanged beta- and alpha-ADR responsiveness after chronic beta 1-ADR blockade. British Journal of Pharmacology, 109, 1053-1058.
10.
Finnish Medical Society Duodecim. (2006). Coronary heart disease (CHD): Symptoms, diagnosis and treatment. In EBM Guidelines. Evidence-Based Medicine [CD-ROM]. Helsinki , Finland: Duodecim Medical Publications Ltd .
11.
Gaballa, M.A., Peppe, K., Lefkowitz, R.J., Aguirre, M., Dober, P.C., & Pennock, et al. (1998). Enhanced vasorelaxation by overexpression of beta-2-adrenergic receptors in large arteries. Journal of Molecular and Cellular Cardiology, 30, 1037-1045.
12.
Gros, R., Benovic, J.L., Tan, C.M., & Feldman, R.D. (1997). G-protein coupled receptor-kinase activity is increased in hypertension. Journal of Clinical Investigation , 99, 2087-2093.
13.
Gros, R., Chorazyczewski, J., Meek, M., Benovic, J.L., Ferguson, S.S.G., & Feldman, R.D. (2000). G-protein-coupled receptor kinase activity in hypertension increased vascular and lymphocyte GRK2 protein expression. Hypertension, 35, 38-42.
14.
Gros, R., Tan, C.M., Chorazyczewski, J., Kelvin, D.J., Benovic, J.L., & Feldman, R.D. (1999). G-protein-coupled receptor kinase expression in hypertension. Clinical Pharmacology and Therapeutics, 65, 545-551.
15.
Hantow, I.N., Koopmans, R.P., & Michel, M.C. (2006). The beta2-adrenoceptor gene and hypertension: Is it the promoter or the coding region or neither? Journal of Hypertension, 24, 1003-1007.
16.
Hindorff, L.A., Heckbert, S.R., Psaty, B.M., Lumley, T., Siscovick, D.S., & Herrington, D.M. (2005). Beta(2)-adrenergic receptor polymorphisms and determinants of cardiovascular risk: The Cardiovascular Health Study. American Journal of Hypertension, 18, 392-397.
17.
Iaccarino, G., Cipolletta, E., Fiorillo, A., Annecchiarico, M., Ciccarelli, M., Cimini, V., et al. (2002). β2-Adrenergic receptor gene delivery to the endothelium corrects impaired adrenergic vasorelaxation in hypertension . Circulation, 106, 349-355.
18.
Jennings, K., & Parsons, V. (1976). A study of labetalol in patients of European, West Indian, and West African origin. British Journal of Clinical Pharmacology, 3, 773S-775S.
19.
Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. (2003). The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure: The JNC 7 report. Journal of the American Medical Association, 289, 2560-2572.
20.
Lacy, C.F., Armstrong, L.L., Golman, M.P., & Lance, L.L. (2005). Drug Information Handbook. Hudson, Ohio: Lexi-Comp.
21.
Michel, M.C., Galal, O., Stoermer, J., & Bock, K.D., & Brodde, O.E. (1989). Alpha- and beta-adrenoceptors in hypertension. II. Platelet alpha 2- and lymphocyte beta 2-adrenoceptors in children of parents with essential hypertension. A model for the pathogenesis of genetically determined hypertension. Journal of Cardiovascular Pharmacology , 13, 432-439.
22.
Middeke, M., Remien, J., & Holzgreve, H. (1984). The influence of sex, age, blood pressure and physical stress on beta 2 adrenoceptor density of mononuclear cells. Journal of Hypertension, 2, 261-264.
23.
Monopoli, A., Conti, A., Forlani, A., & Ongini, E. (1993). β1 and β2 adrenoceptors are involved in mediating vasodilation in the human coronary artery. Pharmacology Research, 27, 273-279.
24.
Naslund, T., Silberstein, D.J., Merrell, W.J., Nadeau, J.H., & Wood, A.J.J. (1990). Low sodium intake corrects abnormality in B-receptor mediated arterial vasodilation in patients with hypertension: Correlation with B-receptor function in vitro. Clinical Pharmacology and Therapeutics, 48, 87-95.
25.
Peuster, M., Fink, C., Reckers, J., Beerbaum, P., & von Schnakenburg, C. (2004). Assessment of subacute inflammatory and proliferative response to coronary stenting in a porcine model by local gene expression studies and histomorphometry. Biomaterials, 25, 957-963.
26.
Pippig, S., Adnexinger, S., Daniel, K., Puzicha, M., Caron, M.G., Lefkowitz, R.J., et al. (1993). Overexpression of betaarrestin and beta-adrenerger receptor kinase augment desensitization of beta 2-adrenergic receptors. Journal of Biological Chemistry, 268, 3201-3208.
27.
Pitcher, J., Lohse, M.J., Codina, J., Caron, M.G., & Lefkowitz, R.J. (1992). Desensitization of the isolated beta 2-adrenergic receptor by beta-adrenergic receptor kinase, cAMP-dependent protein kinase, and protein kinase C occurs via distinct molecular mechanisms . Biochemistry, 31, 3193-3197.
28.
Small, K.M., McGraw, D.W., & Liggett, S.B. (2003). Pharmacology and physiology of human adrenoceptor polymorphisms. Annual Review of Pharmacology and Toxicology , 43, 381-411.
29.
Vandesompele, J., De Preter, K., Pattyn, F., Poppe, B., Van Roy, N., Paepe, A., et al. (2002). Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biology, 3, research0034.1-0031.11.
30.
Veglio, F., Tayebati, S.K., Schiavone, D., Ricci, A., Mulatero, P., Bronzetti, E., et al. (2001). Alpha-1-adrenergic receptor subtypes in peripheral blood lymphocytes of essential hypertensives. Journal of Hypertension, 19, 1847-1854.
31.
Wang, T., & Brown, M.J. (2001). Influence of β1-adrenoceptor blockade on the gene expression of adenylate cyclase subtypes and β-adrenoceptor kinase in human atrium. Clinical Science, 101, 211-214.
32.
Wood, A.J. (2002). Variability in β-adrenergic receptor response in the vasculature: Role of receptor polymorphism. Journal of Allergy and Clinical Immunology, 110, S318-S321.
