John P. Collister - US grants

DESCRIPTION (Adapted from applicant's abstract) This application is based on the hypothesis that changes in salt intake lead to changes in circulating levels of the hormone, angiotensin II (AII). Subsequent alterations in AII levels act via the brainstein site known as the area postrema to create neurogenic changes in medullary sympathetic activity. More specifically, an increase in salt intake will decrease circulating levels of AII via suppression of the renin-angiotensin system (RAS). Decreased concentrations of AII at the area postrema will cause a withdrawal of sympathetic tone to the kidneys and vasculature. Suppression of the RAS along with withdrawal of sympathetic tone allows for the preservation of arterial pressure, as well as sodium and volume homeostasis. It is hypothesized that any intervention in this NaCl-AII- Sympathetic Reflex (during increases in NaCl intake) will result in a lack of salt induced sympathoinhibition and salt induced hypertension. Dr. John Collister received his D.V.M. in 1994 from the Univ. of IL. He is now currently working toward a Ph.D. in the Dept. of Vet. PathoBiology at the Univ. of MN. The applicant has both a strong academic and research background. He has chosen a research career in the biomedical sciences of integrated cardiovascular physiology. During the initial two years of support from this award, Dr. Collister will be under the direct supervision of the sponsor, Dr. John Osborn. During this time, 100% effort will be placed on the proposed research while the candidate completes his Ph.D. thesis. Dr. Osborn has trained successful scientists in the past and is a well known and respected scientist both locally and nationally, in the field of hypertension research. Upon completion of his Ph.D., Dr. Collister will be appointed to an Assistant Professorship within the Dept. of Vet. PathoBiology. At this time, 80% effort will be placed on the proposed research, while other time will be utilized teaching classes within the College of Veterinary Medicine (Anatomy and Physiology). In addition, the advisory committee will meet regularly to discuss research data and future directions. This committee is made up of diverse individuals who are all active and trained researchers in specific areas of the RAS. Dr. Collister will also have the opportunity to interact with individuals from the Departments of Pharmacology, Neuroscience, and Cellular and Integrative Physiology, through attending regular journal clubs and seminars. Upon completion, Dr. Collister will have fully developed into an independent investigator.

DESCRIPTION (provided by applicant): Central nervous system control over long-term blood pressure (BP) regulation is not completely understood. Many investigators have studied the individual roles of the subfornical organ (SFO) and area postrema (AP) in the central effects of Angiotensin II (Angll). Angll is thought to modulate sympathetic nervous system (SNS) activityat these circumventricular organs (CVOs) and regulate blood pressure (BP). This proposal suggests there is redundancy in the actions of Angll via these CVOs. This is the first study to simultaneously examine effects of both endogenous and exogenous Angll at these 2 CVOs. First, we propose endogenous Angll acts via these CVOs. AIM 1: What are the combined roles of the SFO and AP in the long-term effects of endogenous Angll? BP and cardiac output (CO) will be measured in SFOx, APx and XX rats treated with the AT1 antagonist, Iosartan, for 10 days. Furthermore, we propose changing levels of endogenous Angll act via these CVOs to regulate BP. AIM 2: What are the combined roles of the SFO and AP in the maintenance of BP during changes in dietary salt intake? BP and CO will be measured in SFOx, APx and XX rats subjected to 2 week periods of increased and decreased dietary salt. Lastly, we propose chronic Angll hypertension is mediated through effectsat these CVOs. AIM 3: What are the combined roles of the SFO and AP in the prevention of Angll induced hypertension? BP and CO measurements will be made in APx, SFOx, and XX rats during a 10 day infusionof Angll. We predict that XX rats will have an attenuated hypotensive response to Iosartan, dysregulation of BP during changes in dietary salt, and an attenuated Angll mediated hypertension. Furthermore, AIM3a: What are the combined roles of the SFO and AP in Angll induced Fos expression in the RVLM? Fos expression will be measured in the RVLM in APx, SFOx and XX rats subjected to Angll infusion. We predicteither or both the SFO and AP are necessary for Angll induced Fos expression in the RVLM. Our hypothesis is based on the idea that lesioned animals will not be able to alter SNS activity appropriatelyin the same manner as sham rats during the above manipulations, and this will lead to the altered blood pressure responses. In order to address this underlying hypothesis, and link the SNS to the observed changes in blood pressure, we will measure acute depressor responses to the ganglionic blockingagent, hexamethonium, as well as plasma norepinephrine levels in all rats during control and treatment periods. These multiple methods will allow us to determine the sympathetic contribution to vasomotor tone during the observed changes in blood pressure. The results of these studies will greatly enhance our understanding of the central effects of Angll at two specific brain regions, and how these interactions play a role in the long-term control of arterial pressure.