β2‐Adrenergic receptor polymorphism and nitric oxide‐dependent forearm blood flow responses to isoproterenol in humans

Journal of Physiology - Tập 546 Số 2 - Trang 583-589 - 2003
Vesna D. Garovic1, Michael J. Joyner2, Niki M. Dietz2, Eric Boerwinkle3, Stephen T. Turner1
1Division of Hypertension, Department of Internal Medicine, Rochester, MN, USA
2Department of Anesthesiology, Mayo Clinic, Rochester, MN, USA
3Human Genetic Center, University of Texas‐Houston, Health Science Center, Houston, TX, USA

Tóm tắt

Polymorphisms in the gene encoding the β2‐adrenoceptor have been associated with interindividual differences in blood pressure and the diagnosis of hypertension. A common polymorphism resulting in a change from arginine to glycine at amino acid 16 (Arg16 → Gly) enhances agonist‐promoted downregulation of receptor expression in vitro. It is unknown whether genotype‐dependent differences in nitric oxide generation contribute to differences in vasodilator responses to β2‐agonists in vivo. To address this question, venous occlusion plethysmography was used to measure forearm blood flow responses to graded brachial artery infusions of the β‐agonist isoproterenol in 41 healthy normotensive Caucasian adults (mean age (±s.d.) = 29 ± 6 years), who were either Arg16 (n= 18) or Gly16 (n= 23) homozygotes. Compared to Arg16 homozygotes, Gly16 homozygotes demonstrated significantly greater blood flow responses to isoproterenol (P= 0.02). After inhibition of nitric oxide synthase by Nγ‐monomethyl‐l‐arginine, blood flow responses did not differ significantly between genotype groups (P= 0.27). Consequently, effects of the Arg16 → Gly polymorphism on forearm blood flow responses to isoproterenol appear to be dependent on differences in endothelial generation of nitric oxide. In contrast to previous reports based on systemic infusions of β2‐agonists, our findings indicate that regional blood flow responses to locally infused isoproterenol are significantly greater in Gly16 than in Arg16 homozygotes.

Từ khóa


Tài liệu tham khảo

10.1161/01.HYP.37.5.1303

10.1161/01.CIR.101.25.2877

10.1097/00004872-200018020-00006

10.1161/01.HYP.36.3.371

10.1172/JCI115987

10.1161/01.CIR.95.9.2293

10.1113/jphysiol.1994.sp020366

10.1056/NEJMoa010819

10.1073/pnas.97.19.10483

10.1152/jappl.1996.81.4.1807

10.1139/y87-261

10.1172/JCI111255

10.1161/01.HYP.33.6.1425

Green SA, 1993, A polymorphism of the human beta 2‐adrenergic receptor within the fourth transmembrane domain alters ligand binding and functional properties of the receptor, J Biol Chem, 268, 23116, 10.1016/S0021-9258(19)49434-9

10.1021/bi00198a006

10.1093/oxfordjournals.bmb.a070026

10.1016/S0895-7061(00)01188-2

Hoit BD, 2000, Beta2‐adrenergic receptor polymorphisms at amino acid 16 differentially influence agonist‐stimulated blood pressure and peripheral blood flow in normal individuals, Am Heart J, 139, 537

10.1097/00004872-200018060-00005

10.1161/01.HYP.37.2.286

10.1161/01.HYP.30.4.773

10.1161/01.CIR.99.11.1407

10.1093/hmg/7.9.1379

10.1056/NEJM199507203330304

Oates JA, 2001, The Pharmacological Basis of Therapeutics, 871

10.1161/01.CIR.87.5.1468

10.1165/ajrcmb/8.3.334

10.1172/JCI118070

10.1161/01.HYP.27.6.1210

10.1161/01.CIR.94.6.1298

10.1046/j.1523-1755.1998.00926.x

10.1067/mcp.2000.106293