Genetic Determinants of Vasorelaxation to beta-Agonist

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DESCRIPTION (provided by applicant): Blunted vasodilator responses to beta agonist have been implicated in the pathogenesis of hypertension. The vasodilator responses also vary by race, and the genetic basis is not clear. The overall goal of this proposal is to determine genetic variants that underlie the variability in vasodilator response to beta-agonists. In Specific Aim 1, we will test the hypotheses that defective venodilatory response to beta-agonists in hypertension is associated with reduced endothelium-mediated venodilation by nitric oxide, and that allelic variants at gene loci encoding the targets of beta-agonists such as beta-adrenergic receptors (e.g., beta2-AR) and post-receptor signaling (e.g., guanine-nucleotide-binding (G) protein Gs alpha and G-protein-coupled receptor kinases BARK), the enzymes for the synthesis of the beta-agonist epinephrine (e.g., Phenylethanolamine N-methyltransferase, PNMT), and of the beta-agonist effector (e.g., endothelial nitric oxide synthesis, eNOS) underlie and predict the venodilatory response to beta-agonists. Single nucleotide polymorphisms (SNPs) will be determined by resequencing and genotyping the candidate gene loci. The local hand venous response to beta-agonist isoproterenol (ISO) will be compared between normotensives and hypertensives and according to SNPs and/or haplotypes (the array of SNPs at a given chromosome). The preliminary data to date demonstrated that the venodilatory response in hypertension was impaired and related to dysfunction in endothelial NO production, and found that Beta2-AR haplotypes and a common SNP at PNMT promoter region (-353G/A) were associated with blood pressure regulation. In Specific Aim 2, we will test the hypotheses that allelic variants at beta2-AR underlie the lymphocyte response to beta-agonists, and that allelic variant associated with venodilatory response to ISO affect gene function ex vivo and in vitro. Lymphocytes will be isolated and their responses to ISO (e.g., density, sensitivity, and desensitization) will be measured according to individual Beta2-AR SNPs (e.g., Arg16GIy and G1n27G1u) and/or haplotypes. We will correlate the significant allelic variants (e.g., -353 G/A at PNMT promoter) with the biomarkers for the function of genes in vivo such as PNMT enzymatic activity and plasma epinephrine levels, and will isolate or generate these genetic variants and then assess their impact on protein expression and function in cultured cells. This study should define the genetic factors that contribute not only to the development of hypertension but also to the inter-individual variations in pharmacodynamics for both beta-agonists and beta-antagonists.