PARAVENTRICULAR NUCLEUS AND GENDER IN HYPERTENSION

描述：(改编自申请人的摘要)假设为 试验表明，在钠依赖型高血压中，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 减少PVN，减弱激活负责的神经通路 用来增加动脉压。将调查三个具体目标 来检验这一假设。首先，假设雌性老鼠是 防止高血压的发展是因为交感神经 神经系统未被激活将被研究。这些研究将 测定交感-肾上腺神经系统的活动水平 对神经功能进行多项评估，以确定神经活动。这个 第二个目标将集中在PVN作为致病因素的神经化学机制上 高血压过程中的因素。据推测，增加了 NMDA谷氨酸能受体的刺激是由于 GABA的抑制作用。在雌性大鼠中，结果是高血压得到缓解 减少谷氨酸受体的刺激，限制了 动脉压。在第三个目的中，假设血管紧张素II 室旁核内谷氨酸对钠依赖的调节作用 高血压。血管紧张素II在谷氨酸能中的作用 将在雄性和雌性大鼠身上进行兴奋研究，以确定 血管紧张素决定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，五组 动物将被研究：雄性大鼠，雌性大鼠基础雌激素期间 水平(发情间期/发情)，雌性大鼠在雌激素激增期间(发情前期)， 去卵巢雌性大鼠和去卵巢雌性大鼠用药 雌二醇和黄体酮来模拟发情周期。动脉压 将监测有意识的单肾图-8肾包膜高血压 老鼠。GABA、谷氨酸和血管紧张素的药理干预 在PVN中使用微量注射的II系统将显示不同 神经递质功能。微注射研究将得到以下补充 受体放射自显影和微透析实验。团结在一起， 这项工作的结果将为机制的研究提供重要的新发现 钠依赖型高血压。重要的是，对 高血压表现的性别差异将被揭示出来。

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.