BRAIN ANGIOTENSIN II IN THE PATHOGENESIS OF HYPERTENSION

越来越多的证据表明，大脑的肾素-血管紧张素系统可能 在自发性高血压的发展中起作用 高血压大鼠(SHR)。非常重要的一点是，发现慢性 脑室注射转换酶治疗自发性高血压病 抑制剂卡托普利，剂量给药无效 静脉注射可显著延缓高血压的发展。 卡托普利这种降压作用的机制和 脑肾素-血管紧张素系统在自发性高血压中的作用 不能确切地知道。 目前的研究计划建议定义脑血管紧张素的作用。 II(AII)在自发性高血压病中的作用，并确定其作用机制(S)。这项建议 将检验这一假设，即大脑AII通过产生 血管反应性、压力感受性反射活动功能异常 和/或以这种菌株为特征的交感冲动。为此，我们 将使用卡托普利阻断大脑肾素-血管紧张素系统并进行研究 这种阻断对功能异常发展的影响 在SHR。脑血管紧张素可引起血管反应性改变 通过影响促肾上腺皮质激素和加压素的释放。 外周血管反应性研究(有意识的全动物使用 将实施多普勒血流探头和隔离灌流血管床) 以确定皮质酮和/或加压素是否参与 自发性高血压大鼠血管反应性增加的诱导以及 中央给药卡托普利的抑制作用是由于 抑制ACTH和/或加压素。脑血管紧张素可能参与 在SHR中通过改变压力反射功能。这将通过评估来检验 卡托普利对自发性高血压大鼠心脏压力感受性反射控制的影响 心率和血管阻力，并确定是否影响 卡托普利可被AII或加压素逆转。最后， 脑AII可引起SHR交感神经功能的改变。这 将测试评估大脑抑制对AII的影响 交感神经功能与中枢AII给药能力 扭转封锁的影响。这些实验的结果应该是 提供有关脑AII在正常情况下的作用的基本信息 心血管调节以及高血压的发病机制。

Increasing evidence suggests that the brain renin-angiotensin system may play a role in the development of hypertension in the spontaneously hypertensive rat (SHR). Of great importance is the finding that chronic intra-cerebroventricular (icv) treatment of SHR with the converting enzyme inhibitor, captopril, at doses which have no effect when given intravenously significantly attenuates the development of hypertension. The mechanisms underlying this antihypertensive action of captopril and the role of the brain renin-angiotensin system in spontaneous hypertension are not known with certainty. The present research plan proposes to define the role of brain angiotensin II (AII) in SHR and identify its mechanism(s) of action. This proposal will test the hypothesis that brain AII participates in SHR by producing the functional abnormalities in vascular reactivity, baroreflex activity and/or sympathetic drive which characterize this strain. To this end we will employ captopril to block the brain renin-angiotensin system and study the effects of this blockade on the development of functional abnormalities in SHR. Brain angiotensin may produce alterations in vascular reactivity through its ability to affect the release of ACTH and vasopressin. Peripheral vascular reactivity studies (conscious whole animal using Doppler flow probes and isolated perfused vascular beds) will be performed to determine whether corticosterone and/or vasopressin participates in the induction of increased vascular reactivity in SHR and whether the inhibitory effects of centrally administered captopril are due to inhibition of ACTH and/or vasopressin. Brain angiotensin may participate in SHR by altering baroreflex function. This will be tested by assessing the effect of captopril treatment of SHR on baroreflex control of heart rate and vascular resistance and determining whether the effects of captopril are reversed by administration of AII or vasopressin. Finally, brain AII may produce alterations in sympathetic function in SHR. This will be testedly assessing the effects of inhibition of brain AII on sympathetic function and the ability of central AII administration to reverse the effects of blockade. The results of these experiments should provide fundamental information on the role of brain AII in normal cardiovascular regulation as well as in the pathogenesis of hypertension.