This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The Spontaneously Hypertensive Rat (SHR) is the most widely studied model of genetic hypertension, and Wistar Kyoto (WKY) are oftentimes utilized as normotensive controls. I have previously shown that early transient inhibition of the renin-angiotensin system (RAS) in young SHR results in a permanent reduction of blood pressure after drug treatment is withdrawn. My long-term objective is to understand the mechanism(s) involved in this phenomenon. My preliminary findings indicate that SHR transiently treated with an antagonist of the RAS have diminished responses to both ganglionic blockade and to a novel form of stress. To advance this work further, I need to understand the link between the permanent reduction of blood pressure and adaptive behavior of the animals. My collaborators (listed above) have helped in performing behavioral studies to assess anxiety (by elevated-plus-maze) and reactivity (biochemical, as well as pressor responses) to standard stressors such as forced restraint and footshock paradigms. We are also proposing to assess changes in the central RAS by measuring pressor responses to intracerebroventricular infusion of angiotensin II and by performing semiquantitative measures of angiotensin AT1 receptors in cardio-regulatory brain regions. We are postulating that early antihypertensive treatment with an angiotensin converting enzyme inhibitor alters density of AT1 angiotensin receptors and/or responses to angiotensin II in cardio-regulatory regions of the brain. We propose that these alterations of central RAS are linked to reductions in anxiety and reactivity to stressors in SHR, that may ultimately contribute to a permanent reduction of blood pressure.
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