Dopamine is an endogenous catecholamine that has important effects on systemic and renal hemodynamics and sodium homeostasis. Recent evidence suggests substantial alterations in dopaminergic D1-like receptor-mediated renal hemodynamic and natriuretic effects in both human and experimental hypertension. Moreover, these alterations may occur before the onset of hypertension and exhibit evidence of heritability. In addition, marked phenotypic variation in both renal vascular and renal tubular responses to dopamine and other D1-agonists has been observed when these agents are administered experimentally or therapeutically in humans. Recent autonomic/adrenergic response linkage studies in family members by our group and others suggest that locus in the chromosome 5q32-q34 region is responsible for phenotypic variation in blood pressure and other blood pressure-associated """"""""intermediate phenotypes."""""""" This region on chromosome 5q harbors several candidate blood pressure-associated """"""""intermediate phenotypes."""""""" This region on chromosome 5q harbors several candidate loci which could logically contribute to the phenotypic variations observed, including several adrenergic receptors, alpha1B (ADRA1B), beta2 (ADRB2), and dopamine D1 (DRD1) receptors. Recently, we have performed extensive mapping studies within the region of linkage on chromosome 5q, including detailed radiation hybrid mapping, and have found that our peak linkage result corresponds to microsatellite markers which are physically much close to the DRD1 locus than to the other adrenergic receptor candidates in this region. We have re-sequenced the DRD1 locus than to the other adrenergic receptor candidates in this region. We have re-sequenced the DRD1 locus in our cohort and have identified several single nucleotide polymorphisms (SNPs), including SNPs in the 5' regulatory (promoter) region of this gene. These SNPs are in strong linkage disequilibrium, and are present within a consequence sequence for a putative adrenergic receptor leader cistron sequence which may regulate translation and expression of the mature receptor molecule. Thus, we will test the global hypothesis that SNPs in dopaminergic candidate genes (e.g., the DRD1 5' promoter) will be associated with alterations in receptor expression or function, which in turn will result in phenotypic variation in renal and systemic hemodynamics, and, and natriuretic responses, these phenotypic variations will, in turn, become manifest especially during exposure to specific dopaminergic agonists. To accomplish these aims, we will phenotype human subjects comprehensively for renal and systemic hemodynamics at baseline and after the specific D1 agonists, fenoldopam. While we will place high priority on the DRD1 receptor on chromosome 5 because of our linkage results and radiation hybrid mapping, we will also investigate other candidate genes which may participate through dopaminergic pathways and hence may interact with allelic variations in DRD1 or perhaps contribute independently to the overall determination of dopaminergic responses.
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