PARAVENTRICULAR NUCLEUS AND GENDER IN HYPERTENSION

高血压中的室旁核和性别

• 批准号: 6183749
• 负责人: Joseph R Haywood
• 金额: $ 24.92万
• 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/6183749
• 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）假设是 测试结果是，在钠依赖性高血压中，GABA能抑制 下丘脑室旁核的谷氨酸能功能 (PVN) 减少，允许激活下行通路以刺激 交感神经系统。 在雌性大鼠中，谷氨酸能活性是 PVN 中的减少减弱了负责的神经通路的激活 以增加动脉压。 将调查三个具体目标 来检验这个假设。 首先，假设雌性大鼠 预防高血压的发展，因为交感神经 神经系统未激活将被研究。 这些研究将 使用确定交感肾上腺神经系统的活动水平 神经功能的多重评估来定义神经活动。 这 第二个目标将重点关注 PVN 中作为致病因素的神经化学机制 高血压过程中的因素。 假设增加了 NMDA 谷氨酸受体的刺激是由于减少 GABA 的抑制作用。 雌性大鼠的高血压因此而减弱 谷氨酸受体刺激的减少限制了 动脉压。 在第三个目标中，假设血管紧张素 II PVN 中促进谷氨酸介导钠依赖性的作用 高血压。 血管紧张素II对谷氨酸能的贡献 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 对男性和女性的刺激。 为了实现这些目标，五个小组 将研究的动物：雄性大鼠、雌性大鼠在基础雌激素期间 水平（发情间/发情期），雌性大鼠雌激素激增期间（发情前期）， 切除卵巢的雌性大鼠和用以下药物治疗的切除卵巢的雌性大鼠 雌二醇和黄体酮来模拟动情周期。 动脉压 将在有意识的单肾8字形肾包裹高血压中进行监测 老鼠。 GABA、谷氨酸和血管紧张素的药理干预 PVN 中使用显微注射的 II 系统将揭示以下差异： 神经递质功能。 显微注射研究将得到补充 受体放射自显影和微透析实验。 在一起， 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，深入了解基础 高血压表达的性别差异将被揭示。