title: Beta(2)-adrenoceptor polymorphism determines vascular reactivity in humans.
abstract: Altered beta-adrenergic regulation has been reported in individuals with hypertension. The variability in vascular responsiveness to beta-agonists, such as isoproterenol, observed in humans may be explained partially by beta(2)-adrenoceptor polymorphism. Individuals with the Gln27 form of the receptor may show reduced vascular reactivity because of downregulation expression of the receptor in the vasculature. We screened 127 normotensive white subjects, 37 of whom were homozygous for these alleles. Thirty-two subjects (17 Gln27 and 15 Glu27) agreed to receive brachial artery infusions of isoproterenol at doses of 1 to 300 ng. min(-1); forearm blood flow was measured by using venous occlusion plethysmography. Of these subjects, 25 (12 Glu27 and 13 Gln27) received local doses of isoproterenol (0.3 to 30.0 ng. min(-1)) via a dorsal hand vein preconstricted with norepinephrine. Compared with subjects homozygous for the Glu27 allele, subjects with the Gln27 substitution had lower baseline blood flow and, in response to isoproterenol, had a significantly attenuated increase in forearm blood flow. This pattern was more marked in veins. We also studied the relationship between the position 16 polymorphism and vascular reactivity. Homozygotes for Arg16 had significantly lower basal blood flow and attenuated increases in forearm blood flow compared with the Gly16 homozygotes. This was significant in veins but not in arteries. Thus, beta(2)-adrenoceptor genotype determines vascular responses to isoproterenol in forearm resistance vessels and in capacitance vessels. Further studies are necessary to establish whether beta(2)-adrenoceptor polymorphisms are important in the genesis of hypertension.
authors.affiliation: School of Medical and Surgical Sciences, Division of Therapeutics, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, UK. cockcroftjr@cardiff.ac.uk
authors.forename: J R
authors.initials: JR
authors.lastname: Cockcroft
authors.forename: A G
authors.initials: AG
authors.lastname: Gazis
authors.forename: D J
authors.initials: DJ
authors.lastname: Cross
authors.forename: A
authors.initials: A
authors.lastname: Wheatley
authors.forename: J
authors.initials: J
authors.lastname: Dewar
authors.forename: I P
authors.initials: IP
authors.lastname: Hall
authors.forename: J P
authors.initials: JP
authors.lastname: Noon
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000328:Adult; D000704:Analysis of Variance; D001158:Arteries / Q000187:drug effects / Q000502:physiology; D004311:Double-Blind Method; D005542:Forearm / Q000098:blood supply; D006720:Homozygote; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D012039:Regional Blood Flow / Q000502:physiology; D014655:Vascular Resistance / Q000187:drug effects / Q000235:genetics*; D014664:Vasodilation / Q000187:drug effects / Q000235:genetics; D014680:Veins / Q000187:drug effects / Q000502:physiology; D044465:White People
chemical_list: D000318:Adrenergic beta-Agonists; D018343:Receptors, Adrenergic, beta-2; D007545:Isoproterenol