BRAIN AND CARDIAC ANGIOTENSIN II IN HYPERTENSION

主要目的是确定早期、短期ACE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cDNA （AT1 R-AS）对SHR的长期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者先前的研究，这些研究表明，早期短期使用卡托普利（CAP）或早期单次应用AT1 R-AS治疗SHR不仅可以减轻治疗大鼠的高血压，也可以减轻其后代的高血压。要验证的主要假设是，Ang II是高血压表型表达所必需的容许因子，早期干扰这种肽，特别是在大脑或心脏，通过减少其合成和/或影响其受体，可以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1：确定SHR早期短期CAP治疗的长期降压效果是否由于长期减弱的Ang II和/或其受体的产生而传递给治疗大鼠的后代和/或由于抗高血压药物如缓动素（BK）， Ang（1-7）或一氧化氮（NO）的积累而传递给治疗大鼠的后代。目的二：确定早期CAP治疗的长期降压作用是否下调脑内AT1受体亚型（at1r），并由此产生Ang II介导的交感神经系统调节的衰减。目的III：确定早期CAP治疗的长期降压作用是否下调心脏中的at1r，并由此减弱Ang II介导的心血管结构重构作用。目的IV：确定SHR早期at1r反义治疗是否模拟早期短期CAP治疗观察到的脑和心脏受体及其功能的变化。我们将进行组织学，形态学，生化，分子生物学和功能研究，以解决这些假设。该建议解决了一个重要的心血管问题，即脑和心脏肾素-血管紧张素系统在高血压及其后遗症的发展中的作用，以及为什么早期短期ACE治疗或单次早期应用AT1 R-AS对这些系统的早期扰动不仅会导致SHR患者接受这些治疗的高血压发展，而且会对其后代产生永久性影响。这些研究非常新颖，不仅有助于确定治疗高血压的新策略，也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.