The proposed studies are an extension of longitudinal investigations of mechanisms for the development of primary hypertension. They are performed on a biracial cohort of children, adolescents, and young adults who are mostly normotensive. These studies are based on the premise that the pathophysiology of hypertension begins early in life, and further that blood pressure (BP) studies carried out at this age avoid the confounding cardiovascular and renal changes that typically occur when subjects are hypertensive. In the previous period of funding, distinct racial differences relevant to BP regulation were observed; first, longitudinal BP increased over time faster in blacks than in whites; second, aldosterone excretion was lower in blacks than in whites due in part to suppression of the renin-angiotensin system (RAS); and third, the level of serum angiotensinogen was higher and a variant of the angiotensinogen gene (AGT), T235, which has been associated with hypertension, was the predominant allele in the blacks. In the proposed studies, the focus will be principally on the role of sodium retention and how this is regulated by angiotensin II (AII), a product derived from angiotensinogen, and the amiloride-sensitive sodium channel (ENaC), an important site for reabsorption of sodium in the distal nephron. The studies utilize the longitudinal BPs of the cohort - the mean of multiple values as well as the change in BP over time. The cohort will be supplemented through recruitment of additional members and increased participation by parents.
In Specific Aim No. 1 three substudies will be performed: (1) Since the T235 allele may be in linkage disequilibrium with a locus that increases the angiotensinogen level, the applicants will now construct haplotypes with T235 to identify a subset(s) of T235 alleles that associate with a higher angiotensinogen level, and potentially a hypertensinogenic locus on AGT. (2) To examine whether a higher angiotensinogen level in black children is related to race alone or is related specifically to the higher prevalence of hypertension in the parents. (3) Finally, the relation of newly identified variants of genes for ENaC to longitudinal BP, the RAS, and the urinary excretion of aldosterone and potassium to look for molecular variations of this ion channel as contributors to a higher BP will be examined.
Specific Aim No. 2 will be performed in the General Clinical Research Center where the effects of AII on renal hemodynamics and sodium resorption can be examined. Since increases in vascular resistance in the kidney that may be mediated by AII may increase resorption of sodium, the applicants will measure renal blood flow (RBF) to test the hypotheses that RBF is lower in blacks than in whites, and is inversely related to level of angiotensinogen and longitudinal BP. In response to a sodium challenge imposed by an infusion of normal saline, the clearance of endogenous lithium, a measure of AII-directed sodium reabsorption in proximal tubule, and the fractional excretion of sodium, a measure of overall natriuretic capacity, will be examined in relation to race, angiotensinogen level, and longitudinal BP. An ongoing longitudinal study of BP is extended with cross-sectional analyses of potential genetic and renal influences on BP, factors that could contribute to the etiology of primary hypertension.
Showing the most recent 10 out of 50 publications
