PARAVENTRICULAR NUCLEUS AND GENDER IN HYPERTENSION

高血压中的室旁核和性别

• 批准号: 2030192
• 负责人: Joseph R Haywood
• 金额: $ 22.48万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-10 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2030192
• 关键词: angiotensin /renin /aldosterone hypertension; angiotensin II; autoradiography; disease /disorder etiology; estrogens; gamma aminobutyrate; gender difference; glutamate receptor; glutamine; hormone regulation /control mechanism; hypertension; laboratory rat; microdialysis; microinjections; neurochemistry; neuroendocrine system; neuropharmacology; neuroregulation; paraventricular nucleus; progesterone; sympathetic nervous system

DESCRIPTION: (Adapted from the Applicant's Abstract) The hypothesis to be tested is that in sodium-dependent hypertension GABAergic inhibition of glutamatergic function in the paraventricular nucleus of the hypothalamus (PVN) is reduced permitting activation of descending pathways to stimulate the sympathetic nervous system. In female rats, glutamatergic activity is reduced in the PVN attenuating the activation of neural pathways responsible for increasing arterial pressure. Three specific aims will be investigated to test this hypothesis. First, the hypothesis that female rats are protected against the development of hypertension because the sympathetic nervous system is not activated will be studied. These studies will determine the level of activity of the sympathoadrenal nervous system using multiple assessments of neural function to define neural activity. The second aim will focus on neurochemical mechanisms in the PVN as a causative factor in the hypertensive process. It is hypothesized that increased stimulation of NMDA glutamatergic receptors occurs as a result of reduced inhibition by GABA. In female rats hypertension is attenuated as a result of a reduced stimulation of the glutamate receptor limiting the increase in arterial pressure. In the third aim, it is hypothesized that Angiotensin II in the PVN facilitates the effect of glutamate in mediating sodium-dependent hypertension. The contribution of Angiotensin II to glutamatergic excitation will be studied in male and female rats to determine if angiotensin determines the difference in sensitivity to glutamate stimulation in males and females. To implement these aims, five groups of animals will be studied: male rats, female rats during basal estrogen levels (diestrous/estrous), female rats during estrogen surge (proestrus), ovariectomized female rats and ovariectomized female rats treated with estradiol and progesterone to mimic the estrous cycle. Arterial pressure will be monitored in conscious one-kidney figure-8 renal wrap hypertensive rats. Pharmacological intervention of the GABA, glutamate and angiotensin II systems in the PVN using microinjections will reveal differences in neurotransmitter function. Microinjection studies will be complemented by receptor autoradiography and microdialysis experiments. Together, the results of this work will provide important new findings into the mechanisms of sodium-dependent hypertension. Importantly, insights into the basis of gender differences in the expression of hypertension will be revealed.

描述：（改编自申请人的摘要） 测试的是，在钠依赖性高血压中， 下丘脑室旁核的神经递质功能 (PVN)减少，允许下行通路的激活，以刺激 交感神经系统 在雌性大鼠中， 减少PVN，减弱负责的神经通路的激活 用于增加动脉压。 将研究三个具体目标 来验证这个假设 首先，假设雌性大鼠 防止高血压的发展，因为交感神经 神经系统不被激活将被研究。 这些研究将 确定交感肾上腺神经系统的活动水平， 对神经功能进行多重评估以确定神经活动。 的 第二个目标将集中在PVN的神经化学机制作为一个病因， 高血压过程中的因素。 据推测， NMDA能受体的刺激是由于减少的 GABA抑制。 结果，雌性大鼠的高血压减弱 谷氨酸受体的刺激减少限制了 动脉压 在第三个目的中，假设血管紧张素II 在PVN中促进谷氨酸在介导钠依赖性 高血压 血管紧张素II在血管紧张素受体中的作用 将在雄性和雌性大鼠中研究兴奋，以确定是否 血管紧张素决定对谷氨酸敏感性的差异 在男性和女性的刺激。 为了实现这些目标， 将研究动物：雄性大鼠，雌性大鼠在基础雌激素 水平（间情期/发情期），雌激素激增期间的雌性大鼠（发情前期）， 切除卵巢的雌性大鼠和用 雌二醇和孕酮来模拟发情周期。 动脉压 将在清醒的一肾图8肾包裹高血压监测 大鼠 GABA、谷氨酸和血管紧张素的药物干预 使用显微注射的PVN中的II系统将揭示以下方面的差异： 神经递质功能 微注射研究将得到补充， 受体放射自显影和微透析实验。 统称 这项工作的结果将为机制提供重要的新发现， 钠依赖性高血压 重要的是，深入了解 将揭示高血压表达的性别差异。