Tyrosine Hydroxylase Sry and Hypertension

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DESCRIPTION (provided by applicant): Hypertension affects about 25% of individuals in Western are affected more than females in most mammalian populations. Human studies from England, Australia, Japan and Sweden have shown that blood pressure is higher in males with hypertensive fathers compared to those with hypertensive mothers. These findings support our hypothesis that a locus on the Y chromosome can cause blood pressure to increase in an animal genetic model of hypertension as found in humans. A consomic rat strain developed in our laboratory by backcrossing hypertensive SHR and normotensive WKY for over 19 generations has produced a strain that has a Y chromosome from a hypertensive father and the rest of the genome is derived from a normotensive WKY. This unique animal strain has an important locus on the Y chromosome that significantly increases blood pressure. We propose that this locus is the Sry gene and males have at least one mutation in the consomic strain. The main hypothesis of this proposal is that a mutant locus on the Y chromosome is the primary cause of the increased blood pressure through the mechanism of regulating tyrosine hydroxylase, the rate limiting enzyme in catecholamine synthesis. Experiments will be done that examine Sry expression patterns in kidney and adrenal gland before and during the time which blood pressure is increasing. Experiments will be performed to determine if Sry follows a similar expression pattern as seen with tyrosine hydroxylase. Finally, Sry gene delivery to kidney and adrenal gland will demonstrate that blood pressure follows the elevation of Sry and tyrosine hydroxylase. Kidney function will be assessed by renal blood flow and urinary excretion tests before and after Sry gene delivery. Blood pressure will be measured by telemetry and blood flow velocity by Doppler flow probe in conscious animals. The results of these animal studies should enhance our understanding of the mechanism of the Y chromosome effect upon blood pressure in humans.