BRAIN ANGIOTENSIN II IN THE PATHOGENESIS OF HYPERTENSION

越来越多的证据表明，大脑中的肾素-血管紧张素系统可能 在自发性高血压的发展中发挥作用 高血压大鼠（SHR）。 非常重要的是， 用转化酶脑室内（icv）治疗SHR 抑制剂，captopril，在给药时无作用的剂量下 静脉注射显著减弱高血压的发展。 巯甲丙脯酸降压作用的机制和 脑内肾素-血管紧张素系统在自发性高血压中的作用 不知道确切。 目前的研究计划建议确定脑血管紧张素的作用， II（AII）在SHR中的作用，并确定其作用机制。 这项建议 将通过产生脑AII参与SHR的假设来检验 血管反应性、压力反射活动 和/或交感神经驱动，这些都是这种紧张的特征。 为此我们 将采用卡托普利阻断脑肾素-血管紧张素系统， 这种阻断对功能异常发展的影响 在SHR中。 脑血管紧张素可引起血管反应性改变 通过其影响ACTH和加压素释放的能力。 外周血管反应性研究（使用清醒的整个动物） 多普勒血流探头和隔离灌注血管床）将进行 为了确定皮质酮和/或加压素是否参与了 诱导SHR血管反应性增加， 中枢给药的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 通过改变压力感受性反射功能。 这将通过评估进行测试 巯甲丙脯酸对自发性高血压大鼠心脏压力反射控制的影响 率和血管阻力，并确定是否影响 通过给予AII或加压素可逆转卡托普利。 最后， 脑AII可引起SHR交感神经功能的改变。 这 将测试评估抑制大脑AII对 交感神经功能和中央AII管理的能力， 扭转封锁的影响。 这些实验的结果应该 提供关于大脑AII在正常 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.