HUMORAL FACTORS IN GENDER DIFFERENCES IN BP CONTROL

描述(逐字摘自申请表)：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。这个 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有力地证明了雄激素的存在。这个 这项提案的总体目标是调查负责 雄激素引起的血压升高。我们假设中国的性别差异 血压是由雄激素诱导的血浆肾素活性(PRA)和 血管紧张素II(Ang II)，导致钠重吸收增加和 刺激氧化应激，增加超氧化物，减少一氧化氮， 和生产过氧亚硝酸盐和血管收缩因子F2-异前列腺素(IsoP)， 它们增强血管紧张素II的血管收缩作用。 假设将在自发性高血压大鼠(SHR)中进行测试 雄激素通过增加肾素-血管紧张素系统(RAS)来刺激肾素-血管紧张素系统 通过增加超氧化物歧化、减少NO和 通过量化RAS的组成来生产过氧亚硝酸根和异丙基磷 (PRA、Ang II、血管紧张素原、醛固酮)与氧化应激系统 (超氧化物、硝酸盐/亚硝酸盐中的NO、IsoP和亚硝酸酪氨酸化蛋白 肾脏中的过氧亚硝酸根)。在具体目标2中，我们将检验假设 雄激素诱导的RAS激活是调节性别所必需的 自发性高血压患者的血压差异。这一目标将解决RAS是否发挥积极作用的问题 性别差异在血压控制和评价中的作用 雄激素刺激RAS的可能机制，通过固定或 阻止RAS的组件。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调节性别差异 在BP的SI-Fr中，通过抑制合成或阻断氧化成分 压力。在特定的目标4中，将检验雄激素的假设 通过与SHR相似的机制提高正常血压大鼠的血压： 雄激素刺激RAS导致钠重吸收和氧化应激 和NO的失活。这一目标也将解决为什么存在敏感性 自发性高血压患者和正常血压患者对雄激素的升压反应差异 老鼠。

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.