HUMORAL FACTORS IN GENDER DIFFERENCES IN BP CONTROL

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DESCRIPTION (Verbatim from the application): Men and hypertensive male rats have higher blood pressures (BP) than aged-matched women or female rats. The mechanisms responsible for these gender differences are unclear; however, recent studies by ourselves and other have strongly implicated androgens. The overall goal of this proposal is to investigate the mechanisms responsible for androgen-induced increases in BP. We hypothesize that the gender difference in BP is caused by androgen-induced increases in plasma renin activity (PRA) and angiotensin II (Ang II), leading to increases in sodium reabsorption and stimulation of oxidative stress, with increases in superoxide, reduction in NO, and production of peroxynitrite and vasoconstrictor F2-isoprostanes (IsoP), which potentiate the vasoconstrictor actions ofAng II. In Specific Aim 1 the hypothesis will be tested in spontaneously hypertensive rats (SHR) that androgens stimulate the renin-angiotensin system (RAS) by increasing PRA which stimulates oxidative stress with increases in superoxide, reduction of NO and production of peroxynitrite and IsoP, by quantifying the components of the RAS (PRA, Ang II, angiotensinogen, aldosterone) and oxidative stress systems (superoxide, nitrate/nitrite for NO, IsoP, and nitrotyrosinated proteins in kidney for peroxynitrite). In Specific Aim 2, we will test the hypothesis that androgen-induced activation of the RAS is necessary to mediate the gender differences in BP in SHR. This aim will address whether the RAS plays an active or permissive role in the gender differences in BP control and evaluate possible mechanisms by which androgens could stimulate the RAS, by fixing or blocking components of the RAS. In Specific Aim 3, we will test the hypothesis that components of the oxidative stress pathway mediate the gender differences in BP in SI-fR, by inhibiting synthesis or blocking the components of oxidative stress. In Specific Aim 4, the hypothesis will be tested that androgens increase BP in normotensive rats by similar mechanisms as found in SHR: androgens stimulate the RAS leading to sodium reabsorption and oxidative stress and inactivation of NO. This aim will also address why there are sensitivity differences in the pressor responses to androgens between SHR and normotensive rats.