2 Adrenoceptor Functional Gene Variants, Obesity, and Blood Pressure Level Interactions in the General Population (original) (raw)
Related papers
Beta-2 adrenergic receptor diplotype defines a subset of salt-sensitive hypertension
Hypertension, 2006
Two genetic variants of the beta-2 adrenergic receptor, 46G>A and 79C>G, affect agonist-mediated receptor downregulation and vascular reactivity. We determined whether these variants were associated with hypertension, per se, blood pressure response to dietary sodium, 2 forms of salt-sensitive hypertension (low renin and nonmodulation), and the activity of the renin-angiotensin-aldosterone system. Included are 280 hypertensive and 65 normotensive white subjects who had the 2 beta-2 adrenergic receptor genotypes available. Of all subjects, 171 hypertensive and 48 normotensive subjects had complete data for intermediate phenotyping and blood pressure evaluation on high- and low-sodium balance. The beta-2 adrenergic receptor variants were not associated with hypertension per se. However, among hypertensive subjects, the change (from low to high sodium balance) in mean arterial pressure differed significantly by genotype and by diplotype. Compared with all of the other diplotypes ...
-2 Adrenergic Receptor Diplotype Defines a Subset of Salt-Sensitive Hypertension
Hypertension, 2006
Two genetic variants of the -2 adrenergic receptor, 46GϾA and 79CϾG, affect agonist-mediated receptor downregulation and vascular reactivity. We determined whether these variants were associated with hypertension, per se, blood pressure response to dietary sodium, 2 forms of salt-sensitive hypertension (low renin and nonmodulation), and the activity of the renin-angiotensin-aldosterone system. Included are 280 hypertensive and 65 normotensive white subjects who had the 2 -2 adrenergic receptor genotypes available. Of all subjects, 171 hypertensive and 48 normotensive subjects had complete data for intermediate phenotyping and blood pressure evaluation on high-and low-sodium balance. The -2 adrenergic receptor variants were not associated with hypertension per se. However, among hypertensive subjects, the change (from low to high sodium balance) in mean arterial pressure differed significantly by genotype and by diplotype. Compared with all of the other diplotypes combined, 46AA/79CC was associated with a greater change in blood pressure. Furthermore, this diplotype was associated with low-renin (LR) hypertension (identifying 32% of the LR hypertensives), higher plasma aldosterone, and lower plasma renin and serum potassium levels. In conclusion, the 46AA/79CC diplotype is associated with greater blood pressure response to dietary sodium and higher odds of LR hypertension. We propose that the mechanism for the observed association is inadequate suppression of aldosterone with salt intake, implicating the -2 adrenergic receptor in the regulation of aldosterone secretion. This hypothesis was confirmed in isolated glomerulosa cells, where -2 adrenergic receptor stimulation increased aldosterone secretion, whereas blockade reduced the stimulated aldosterone response. Importantly, this association could only be detected with an intermediate and not a distant phenotype. (Hypertension. 2006;48:892-900.) Key Words: -2 adrenergic receptor Ⅲ hypertension Ⅲ salt-sensitive hypertension Ⅲ low-renin hypertension Ⅲ single nucleotide polymorphisms Ⅲ haplotypes Ⅲ diplotypes
Hypertension, 1999
Recent evidence suggests that the prodownregulatory Gly16 allele of the -2 adrenergic receptor (-2 AR) is associated with essential hypertension in African Caribbeans. To further investigate the effect of the glycine (Gly)16 and arginine (Arg)16 -2 AR variants on hemodynamics, we investigated the agonist-mediated in vivo vasodilation in normotensive Austrian Caucasians and analyzed the results with respect to the Gly16/Arg16 polymorphism. Fifty-seven normotensive men, 20 to 32 years of age with body mass index of 18.7 to 29.9 kg/m 2 , were genotyped for the Arg16/Gly16 -2 AR alleles. All 15 Gly16/Gly16 subjects, all 12 Arg16/Arg/16 subjects, and 27 of 30 heterozygous subjects underwent hemodynamic measurements while supine after an overnight fast. The observers were unaware of the subjects' genotypes. The subjects received a graded infusion of the selective -2 AR agonist salbutamol (0.07, 0.14, and 0.21 g/kg per minute, respectively), each dose over 8 minutes. Stroke volume and blood pressure were determined continuously by means of impedance cardiography and oscillometry, respectively. The last 4 minutes of each infusion were evaluated statistically. Basal mean blood pressure was higher in the Gly16/Gly16 subjects compared with Arg16/Arg16 subjects (meanϮSD: 81.6Ϯ6.14 versus 75.2Ϯ4.93 mm Hg, PϽ0.01). Homozygous Gly16 subjects showed a significantly decreased vasodilation during the first dose of salbutamol infusion compared with Arg16/Arg16 subjects (⌬total peripheral resistance index Ϫ17.9Ϯ14.4 versus Ϫ30.6Ϯ8.3%, PϽ0.01) despite increased sympathetic counterregulation in the Arg16/Arg16 group (⌬heart rate ϩ16.9Ϯ7.0% versus ϩ8.6Ϯ7.0%, PϽ0.01; ⌬cardiac index ϩ39.5Ϯ18.5% versus 21.4Ϯ18.8%, PϽ0.05). Our results provide additional evidence that the Gly16/Arg16 alleles of the -2 AR are intimately related to blood pressure regulation and deserve further studies in the pathogenesis of essential hypertension. (Hypertension. 1999;33:1425-1430.)
Overview of the role of B2-adrenergic receptor variants in human hypertension
2014
Essential hypertension isa complex traitto whichmultifactorial origin arising from an interaction between genetic and environmental factorscontribute interactively. Consequently, the identification of genes related to hypertension is complicated by the heterogeneity of its causes and the possibility that various genes with moderate impacts, probably acting in a same manner, affect blood pressure and the occurrence of hypertension. Multiple studies have suggested that variation within the β2-adrenergic receptor (ADRB2) is implicated in blood pressure regulation and the development of hypertension. The evidence for ADRB2 gene association with hypertension is not conclusive. There are conflicting reports on the association of these polymorphisms with hypertension. Several reports have suggested the association of the ADRB2 variants with the prevalence of hypertension and systolic blood pressure (BP)whilst others refuted the association. The role of these findings is reviewed here, and ...
Altered Beta2 Adrenergic Receptor Gene Expression in Human Clinical Hypertension
Biological Research for Nursing, 2009
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 subjects' beta 2-adrenergic receptor gene expression in this tissue.
Altered renal alpha 2-adrenergic receptor regulation in genetically hypertensive rats
Hypertension, 1982
Renal a, and a,-adrenergk receptors were quantified In Dahl salt-sensitive and wit-resistant rats, in Okamoto-Aokl spontaneously hypertensire rats (SHR), in Wlstar Kyoto "nonnotensire" (WKY), and in Charles River rats made hypertensive by the Grollman ligature technique and by DOC-NaG administration after unilateral nephrectomy. The effect of high dietary Nad on renal a receptors was studied in Dahl, SHR, and WKY rats. Renal a, and <x t receptor densities were higher (p < 0.05) in SHR and in Dahl salt-sensitive rats than in their nonnotenslve controls. High dietary sodium increased renal a, receptors and blood pressure in SHR, WKY and Dahl salt-sensitive, but not in resistant Dahl rats. A study of time relationships revealed that the increase in renal a, receptors preceded most of the blood pressure elevation due to high dietary sodium. Renal aadrenergic receptor densities of surgical (Grollman) and endocrine (DOC-NaG) forms of rat hypertension were not different from nonnotensive controls. Thus, renal a, receptor density and increase thereof by dietary sodium may be: 1) a biochemical marker for genetic forms of hypertension in the rat, and 2) closely linked to the basic mechanism of high blood pressure. (Hypertension 4 (suppl II): II-188-II-192, 1982) KEY WORDS • dietary sodium • genetically hypertensive rats • renal a-adrenergic receptor regulation • spontaneously hypertensive rats • hypertensive mechanism genetic regulation of a receptors I NTACT renal sympathetic nerves are essential for the development of high blood pressure in genetic 1 and nongenetic 1 forms of rat hypertension. Sectioning of renal nerves increases urinary sodium excretion." Activation of adrenergic receptors in conscious dogs by renal arterial infusion of norepinephrine induces high blood pressure as long as the infusion is sustained. 6 Thus, adrcnergic receptors have some effect on the kidney that causes high blood pressure, possibly through renal retention of sodium. Yet excess activity of the sympathetic nervous system, as indicated by plasma norepinephrine levels, is not present in many patients with essential hypertension. 7 Thus, we were interested in the possibility that animal models that are supposedly models of essential hypertension*' * might have altered renal a-adrenergic receptors in some way that might mediate an
Circulation: Cardiovascular Genetics, 2011
Background-␣ 2A-Adrenoceptors (␣ 2A-ARs) have important roles in sympathetic cardiovascular regulation. Variants of ADRA2A affect gene transcription and expression and are associated with insulin release and risk for type 2 diabetes. We examined whether ADRA2A variants are also associated with cardiovascular responses to the selective ␣ 2-ARagonist dexmedetomidine. Methods and Results-Seventy-three healthy subjects participated in a placebo-controlled, single-blind study. After 3 infusions of placebo, subjects received 3 incremental infusions of dexmedetomidine (cumulative dose, 0.4 g/kg). Primary outcomes were changes in systolic blood pressure (SBP) and plasma norepinephrine concentrations, measured as difference of the area-under-the-curve during placebo and dexmedetomidine infusions (⌬AUC). We used multiple linear regression analysis to examine the associations between 9 ADRA2A tagging variants and 5 inferred haplotypes and ⌬AUC after adjustment for covariates. Homozygous carriers of rs553668 and the corresponding haplotype 4, previously associated with increased ␣ 2A-AR expression, had a 2.2-fold greater decrease in AUC SBP after dexmedetomidine (adjusted Pϭ0.006); similarly, the maximum decrease in SBP was 24.7Ϯ8.1 mm Hg compared with 13.6Ϯ5.9 mm Hg in carriers of the wild-type allele (Pϭ0.007). Carriers of haplotype 3, previously associated with reduced ␣ 2A-AR expression, had a 44% smaller decrease in AUC SBP (Pϭ0.013). Haplotype information significantly improved the model predicting the decrease in SBP (PϽ0.001). There were similar but nonsignificant trends for diastolic blood pressure and heart rate. Genotypes were not significantly associated with norepinephrine responses. Conclusions-Common ADRA2A variants are associated with the hypotensive response to dexmedetomidine. Effects of specific variants/haplotypes in vivo are compatible with their known effects on gene expression in vitro. (Circ Cardiovasc Genet. 2011;4:179-187.) Key Words: receptors, adrenergic, alpha Ⅲ genetic polymorphism Ⅲ pharmacogenetics Ⅲ receptor Ⅲ variability in drug response A lpha 2A-Adrenoceptors (␣ 2A-ARs) are important regulators of sympathetic tone through central and peripheral (presynaptic) sympathetic inhibition. They are also directly involved in several homeostatic functions, including contraction and relaxation of vascular smooth muscle, control of vigilance, anxiety and stress-related behaviors, pain perception, platelet aggregation, lipolysis, and insulin release. Genetically engineered mice that do not express the ␣ 2A-AR gene (ADRA2A) have a hyperadrenergic phenotype with increased blood pressure, heart rate, and plasma norepinephrine concentrations and develop cardiac hypertrophy and heart failure. 1-4 Moreover, ADRA2A knockout mice do not decrease blood pressure in response to an ␣ 2-AR-agonist such as clonidine. 1 Clinical Perspective on p 187 We and others have systematically defined genetic variation and the haplotype structure of ADRA2A. 5,6 Some of the variants identified have distinct functional effects on receptor expression or function in vitro. 6-8 However, studies to define the functional significance of ADRA2A genetic variation in cardiovascular regulation in vivo have yielded inconsistent results. Some studies have found associations between ADRA2A variants and hypertension, 9-11 whereas others, including 2 genome-wide association studies, have not. 12-15 Blood pressure is regulated by many factors and mechanisms, and the contributions of single genetic variants to
Decreased blood pressure response in mice deficient of the 1b-adrenergic receptor
Proceedings of the National Academy of Sciences, 1997
To investigate the functional role of different ␣ 1 -adrenergic receptor (␣ 1 -AR) subtypes in vivo, we have applied a gene targeting approach to create a mouse model lacking the ␣ 1b -AR (␣ 1b ؊͞؊). Reverse transcription-PCR and ligand binding studies were combined to elucidate the expression of the ␣ 1 -AR subtypes in various tissues of ␣ 1b ؉͞؉ and ؊͞؊ mice. Total ␣ 1 -AR sites were decreased by 98% in liver, 74% in heart, and 42% in cerebral cortex of the ␣ 1b ؊͞؊ as compared with ؉͞؉ mice. Because of the large decrease of ␣ 1 -AR in the heart and the loss of the ␣ 1b -AR mRNA in the aorta of the ␣ 1b ؊͞؊ mice, the in vivo blood pressure and in vitro aorta contractile responses to ␣ 1 -agonists were investigated in ␣ 1b ؉͞؉ and ؊͞؊ mice. Our findings provide strong evidence that the ␣ 1b -AR is a mediator of the blood pressure and the aorta contractile responses induced by ␣ 1 agonists. This was demonstrated by the finding that the mean arterial blood pressure response to phenylephrine was decreased by 45% in ␣ 1b ؊͞؊ as compared with ؉͞؉ mice. In addition, phenylephrine-induced contractions of aortic rings also were decreased by 25% in ␣ 1b ؊͞؊ mice. The ␣ 1b -AR knockout mouse model provides a potentially useful tool to elucidate the functional specificity of different ␣ 1 -AR subtypes, to better understand the effects of adrenergic drugs, and to investigate the multiple mechanisms involved in the control of blood pressure.