BRAIN AND CARDIAC ANGIOTENSIN II IN HYPERTENSION

本研究的主要目的是确定早期、短期的血管紧张素转换酶抑制剂治疗或单次心内注射血管紧张素II AT1受体亚型反义基因(AT1R-AS)对自发性高血压大鼠持续降压和心脏保护作用的机制。这一目标是基于我们和其他研究人员之前的研究，该研究表明，早期、短期使用卡托普利(CAP)或早期、单一应用AT1受体-AS治疗SHR不仅可以减轻治疗大鼠的高血压，还可以减轻其后代的高血压。需要检验的主要假设是，Ang II是高血压表型表达所必需的允许因子，早期扰乱这种多肽，特别是在大脑或心脏，通过减少其合成和/或影响其受体，将防止治疗大鼠及其后代的高血压表达。这个项目有四个具体目标。目的：探讨早期、短期CAP治疗自发性高血压大鼠(SHR)的持久降压效应是否由于传递给子代的Ang II及其受体产生的慢性减弱和/或传递给子代的降压药如缓激肽(BK)、Ang(1-7)或一氧化氮(NO)的积聚所致。目的II：探讨CAP早期降压作用是否下调脑内AT1受体亚型(AT1R)，从而减弱Ang II对交感神经系统的调节作用。目的：探讨CAP早期降压作用是否下调心脏血管紧张素Ⅱ受体(AT1R)，从而减弱Ang II介导的心血管结构重塑效应。目的：探讨早期AT1R反义治疗在自发性高血压大鼠(SHR)中是否能模拟CAP早期短期治疗所观察到的脑和心脏受体的变化及其功能。我们将进行组织学、形态学、生化、分子生物学和功能研究，以解决这些假说。该提案解决了一个重要的心血管问题，即大脑和心脏肾素-血管紧张素系统在高血压及其后遗症的发展中所起的作用，以及为什么早期、短期的ACE治疗或单一的AT1 R-AS早期应用对这些系统的早期扰动会导致持久的影响，不仅在接受这些治疗的自发性高血压患者的高血压发展中，而且在他们的后代中。这些研究具有很高的新颖性，不仅有助于确定治疗高血压的新策略，还有助于确定预防高血压的新策略。

The major goal is to identify mechanisms underlying the prolonged antihypertensive and cardio-protective effects of early, short- term ACE inhibitor therapy or single intracardiac injection of the angiotensin II AT1 receptor subtype antisense cDNA (AT1 R-AS) to SHR. This goal is based on previous studies by us and other investigators showing that early, short-term therapy with captopril (CAP) or early, single-application of AT1 R-AS to SHR attenuated hypertension not only in treated rats but in their offspring as well. The major hypothesis to be tested is that Ang II is a permissive factor necessary for expression of the hypertensive phenotype and that early perturbation of this peptide, particularly in brain or heart, either by decreasing its synthesis and/or effecting its receptors would prevent expression of hypertension in treated rats as well as their offspring. There are four Specific Aims to this project. Aim I: To determine whether or not the prolonged antihypertensive effect of early, short-term CAP therapy in SHR is due to chronically attenuated production of Ang II and/or its receptors which is passed on to offspring of treated rats and/or due to accumulation of antihypertensive agents such as bradykinin (BK), Ang (1-7) or nitric oxide (NO) which are passed on to offspring of treated rats. Aim II: To determine whether or not the prolonged antihypertensive effect of early CAP treatment down-regulates the AT1 receptor subtype (AT1 R) in brain and, with it, produces an attenuation of Ang II mediated modulation of the sympathetic nervous system. Aim III: To determine whether the prolonged antihypertensive effect of early CAP treatment down-regulates AT1 R in heart and, with it, produces an attenuation of Ang II mediated effects on cardiovascular structural remodeling. Aim IV: To determine whether or not early AT1 R antisense therapy in SHR mimics changes in brain and cardiac receptors and their function observed with early, short-term CAP therapy. We will perform histological, morphological, biochemical, molecular biological and functional studies to address there hypotheses. The proposal addresses an important cardiovascular problem, that of the role of brain and cardiac renin-angiotensin systems in the development of hypertension and its sequelae and why early perturbation of these systems with early, short-term ACE therapy or a single early application of AT1 R-AS leads to a permenant effect not only in the development of hypertension in SHR subjected to these treatments but also in their offspring. These studies are highly novel and could help to define new strategies not only for the treamtent of hypertension but its prevention as well.