The long term objectives of this application are to understand the mechanisms by which the Y chromosome from spontaneously hypertensive rats (SHR) produces a significant blood pressure rise. The Y chromosome blood pressure effect has now been documented in two other independent laboratories but the genetic and physiological mechanisms are not known. There appears to be both sympathetic nervous system (SNS) and androgen components to the Y mediated blood pressure effect. This research will benefit our understanding of one of the genetic components of hypertension and parallels what is observed in human populations.
The specific aims will focus on: l) how the SNS may influence testicular development, vascular reactivity and renal metabolism of norepinephrine, 2) if gonadotropin releasing hormone may be released early due to the Y chromosome, 3) if the Y chromosome enhances salt sensitivity, 4) identification and cloning of the heat shock protein sequence on the Y chromosome and 5) determination of the mechanism of the Y chromosome influence on steroid sulfatase in specific tissues.
These aims will be accomplished by using both physiological, genetic and molecular techniques. Blood pressure will be measured by telemetry in several studies throughout' the prepubertal and pubertal stages during which blood pressure rapidly rises. molecular studies measuring components of the renin angiotensin system in testes and kidney will be examined and heat shock protein expression will be determined in relevant target organs, such as, aorta, resistance 'vessels, kidney, heart and adrenal glands. Biochemical measurements of indices of the SNS will evaluate the mechanism of elevated adrenergic responsiveness (increased norepinephrine content, release, turnover) in target' organs influencing blood pressure. in some experiments the genetically testicular feminized male will be studied to determine the interaction of the Y chromosome, androgens, androgen receptor and the SNS upon blood pressure. The results of these studies should enhance our understanding of the mechanism of the Y chromosome effect upon blood pressure.
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