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 AT 1受体亚型反义cDNA（AT 1 R-AS）对SHR的长期降压和心脏保护作用的潜在机制。 这一目标是基于我们和其他研究人员以前的研究，表明早期，短期治疗与巯甲丙脯酸（CAP）或早期，单一应用AT 1 R-AS SHR衰减高血压不仅在治疗大鼠，但在他们的后代以及。 待检验的主要假设是，Ang II是高血压表型表达所必需的容许因子，并且该肽的早期扰动，特别是在脑或心脏中，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中高血压的表达。该项目有四个具体目标。 目标一：确定早期、短期CAP治疗SHR的长期降压作用是否是由于长期减弱Ang II和/或其受体的产生，并将其传递给治疗大鼠的后代，和/或由于降压药如缓激肽（BK）、Ang（1-7）或一氧化氮（NO）的蓄积，并将其传递给治疗大鼠的后代。 目标二：确定早期CAP治疗的长期抗高血压作用是否下调脑中的AT 1受体亚型（AT 1 R），并随之产生Ang II介导的交感神经系统调节的减弱。 目标三：确定早期CAP治疗的长期降压作用是否下调心脏中的AT 1 R，并随之产生Ang II介导的对心血管结构重塑的作用的减弱。 目标四：确定SHR早期AT 1 R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，生物化学，分子生物学和功能研究来解决这些假设。该提案解决了一个重要的心血管问题，即脑和心脏的肾素-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AT 1 R-AS对这些系统的早期扰动不仅在接受这些治疗的SHR的高血压发展中，而且在其后代中产生永久性影响。 这些研究是非常新颖的，可以帮助确定新的策略，不仅治疗高血压，但它的预防以及。

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.