This proposal is to continue studies on the brain renin-angio-tensin system. In the first grant, studies were carried out to establish the existence of angiotensin II in the brain by immunocyto-chemistry, radioimmunoassay and high performance liquid chromatography. In the next grant period, it is proposed to continue these studies by investigating the functional role of brain angiotensin. It is planned to use both in vivo and in vitor experiments carried out in a complimentary fashiion in order to understand more about the basic mechanisms involved. Because there may be numerous functions of brain angiotensin, we hope to reduce the complexity of the problem by working on the hypothesis that a function of brain angiotensin is to control volume homeostasis. 1) Using the HPLC and RIA and an Ang II antibody that we have developed, we shall apply various physiological stimuli that are volume related and measure the effect on brain levels of ANG II will be carried out in primary cell culture and an attempt will be made to answer the question of whether Ang II is made intracellularly as a product of the renin-angiotensin cascade. Brain slices and a push-pull technique will be used to study release of Ang II under physiological stimuli. 3) Based on evidence that Ang II stimulates the nuclear tractus solitarius (NTS), experiments are proposed to study the actions of Ang II on the NTS and its involvement in the baroreceptor reflex. 4) The second main hypothesis of this work has been that SHR rats have a hyperactive brain Ang II. This is to be tested by applying the above experiments to the SHR and normotensive strains. In addition, longterm infusions of Ang II will be used to model the hypothesis of an overactive brain angiotensin system. 5) In collaboration with Dr. Bodor, we will manufacture new analogues of Ang II that can cross the blood brain barrier in order to find a new drug that can cause prolong inhibition of Brain Ang II.
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