β ₂ -Adrenoceptor Polymorphism Determines Vascular Reactivity in Humans

Abstract

Abstract-Altered ␤-adrenergic regulation has been reported in individuals with hypertension. The variability in vascular responsiveness to ␤-agonists, such as isoproterenol, observed in humans may be explained partially by ␤ 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 ⅐ min Ϫ1 ; 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 ⅐ min Ϫ1) 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, ␤ 2 -adrenoceptor genotype determines vascular responses to isoproterenol in forearm resistance vessels and in capacitance vessels. Further studies are necessary to establish whether

Haplotype association analysis of the polymorphisms Arg16Gly and Gln27Glu of the adrenergic β2 receptor in a Swedish hypertensive population

“…Stimulation of b 2 ARs in the vasculature results in vasodilation. 1 Several polymorphisms have been described in the gene for the b 2 AR. The A46G and the C79G polymorphisms are common polymorphisms and both result in amino-acid substitutions of the b 2 ARs, Arg16Gly and Gln27Glu, respectively.…”

“…The positions are located in the amino terminus of the receptor and seem to influence the degree of downregulation of the receptor, 2 which may affect vascular reactivity. 1 b 2 AR polymorphisms have been associated with increased risk for cardiovascular disease through intermediate end points such as body mass index (BMI), 3 hypertension, 3,4 prevalence of diabetes mellitus type II. 4 Polymorphisms in the gene for the b 2 AR have also been reported to be associated with excess coronary events.…”

Arg347Cys polymorphism of α1A-adrenoceptor gene is associated with blood pressure response to nifedipine GITS in Chinese hypertensive patients

“…As the functional implications of the Arg16Gly and Gln27Glu polymorphisms were revealed in vitro, their effects on the agonist-induced vasodilator response have also been investigated in vivo, and the results were controversial. 19,[20][21][22][23] Moreover, there was also no significant association detected between the blood pressure response to hydrochlorothiazide or atenolol and the Arg16Gly polymorphism in several studies. 24,25 An attenuation of b-adrenergic function and a potentiation of a-adrenergic function in cardiovascular tissues have been shown in hypertensive patients, suggesting the development of a postsynaptic a1 function dominance during the development and evolution of hypertension.…”

β2-Adrenergic receptor gene variants and risk for autism in the AGRE cohort

“…19 The effect of these genotypes on receptor responsiveness, desensitization and downregulation has been investigated in vivo. Vascular responsiveness (forearm blood flow and hand vein dilation) to ADRB2 agonists 20,21 and mental stress or exercise 22 appears to be higher among Glu27 homozygotes in experimental situations involving healthy adult volunteers. Studies using the same agonist have also found higher responsiveness among Gly16 homozygotes versus Arg16 homozygotes or heterozygotes 20,23 although not uniformly.…”

“…Vascular responsiveness (forearm blood flow and hand vein dilation) to ADRB2 agonists 20,21 and mental stress or exercise 22 appears to be higher among Glu27 homozygotes in experimental situations involving healthy adult volunteers. Studies using the same agonist have also found higher responsiveness among Gly16 homozygotes versus Arg16 homozygotes or heterozygotes 20,23 although not uniformly. 21 Additionally, Gly16 homozygotes were resistant to desensitization of vascular response (regardless of position 27 amino acid), 21 and showed delayed onset, in the short term, of desensitization of cardiac response 24 and of downregulation of lymphocyte receptor density.…”