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 I V: 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.
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