HUMORAL FACTORS IN GENDER DIFFERENCES IN BP CONTROL

描述（来自申请的逐字描述）：男性和高血压雄性大鼠 血压（BP）高于年龄匹配的女性或雌性大鼠。的 造成这些性别差异的机制尚不清楚;然而， 我们和其他人最近的研究强烈暗示了雄激素。的 这项建议的总体目标是调查负责机制， 雄激素引起的血压升高我们假设， BP是由雄激素诱导的血浆肾素活性（PRA）增加引起的， 血管紧张素II（Ang II），导致钠重吸收增加， 刺激氧化应激，增加超氧化物，减少NO， 以及产生过氧亚硝酸盐和血管收缩剂F2-异前列腺素（IsoP）， 增强血管紧张素II的血管收缩作用。具体目标1 将在自发性高血压大鼠（SHR）中检验这一假设， 雄激素通过增加PRA刺激肾素-血管紧张素系统（RAS）， 刺激氧化应激，增加超氧化物，减少NO， 通过定量RAS的组分生产过氧亚硝酸盐和IsoP (PRA、血管紧张素Ⅱ、血管紧张素原、醛固酮）和氧化应激系统 （超氧化物，硝酸盐/亚硝酸盐的NO，IsoP，和硝基酪氨酸蛋白质， 肾脏过氧亚硝酸盐）。在具体目标2中，我们将检验以下假设： 雄激素诱导的RAS激活是介导性别差异所必需的。 SHR的血压差异。这一目标将解决RAS是否发挥积极作用， 在血压控制和评价中的性别差异 雄激素刺激RAS的可能机制，通过固定或 RAS的阻塞组件。在具体目标3中，我们将检验假设 氧化应激途径的组成部分介导了性别差异， 在SI-fR中的BP中，通过抑制氧化还原酶的合成或阻断氧化还原酶的组分， 应力在具体目标4中，将检验雄激素 通过与SHR中发现的类似机制增加血压正常大鼠的血压： 雄激素刺激RAS，导致钠重吸收和氧化应激 这一目标也将解决为什么有敏感性 自发性高血压大鼠与正常血压大鼠对雄激素升压反应的差异 大鼠

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.