ROLE OF TISSUE ANGIOTENSINS IN THE MEDULLA OBLONGATA

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This project will test two hypotheses. First, outflow of vasomotor neurons of the rostral ventrolateral medulla (RVLM) of Ren-2 transgenic (TG) rats is augmented by angiotensin- and vasopressin-containing pathways. Second, angiotensin and vasopressin inputs to cardiovascular neurons of the nucleus tractus solitarii (nTS) and the RVLM attenuate baroreceptor reflex control of blood pressure and augment sympathetic nerve activity in TG rats. To test these hypotheses, we propose the following specific aims. 1. Describe the brainstem and hypothalamic nuclei that provide either angiotensin- or vasopressin-containing projections to presympathetic neurons of the RVLM. Retrograde tract tracing and immunocytochemical techniques will be used to define these neuroanatomical pathways. Results of these experiments will provide a neuroanatomical basis for interpreting the physiologic and neuropharmacologic experiments of the following specific aims. 2. Demonstrated that angiotensin-containing pathways to the nTS and RVLM attenuate baroreflex control of heart rate and sympathetic nerve activity in TG rats. The receptor subtypes responsible for this action of Ang II or other Ang peptides will be characterized by using receptor subtype selective antagonists. We will also demonstrate that angiotensin- containing pathways to the RVLM result in enhanced sympathetic outflow in TG rats. 3. Demonstrate that vasopressin-containing pathways to the nTS and RVLM contribute to enhanced sympathetic outflow in TG rats. Specifically, we will attempt to show that vasopressin-containing pathways to the nTS attenuate normal baroreflex function whereas vasopressin-containing pathways to the RVLM provide excitatory drive to presympathetic neurons of the RVLM. We will also test the possibility that vasopressin-containing pathways to RVLM neurons attenuate baroreceptor reflex control of sympathetic nerve activity. The results of these studies will define central neural pathways and mechanisms by which the brain renin angiotensin system can contribute to impaired baroreceptor reflex function and augmented activity of the sympathetic nervous system. By conducting these experiments in Ren-2 TG rats we will better assess the role of the brain renin angiotensin system on central neural control of cardiovascular function because key components of the renin angiotensin system (i.e. renin and angiotensin peptides) are over- expressed in this model.