In addition to its classical role as an endocrine system, the renin- angiotensin system (RAS) exists in a number of individual tissues, resulting in the local synthesis, release, and action of angiotensin II (ANG-II). The RAS in the brain through the activation of AT1 receptors has been hypothesized to contribute to the regulation of cardiovascular (CV) function through its effects on central sympathetic nerve outflow and on secretion of vasoactive pituitary hormones including vasopressin, and may play a role in the pathogenesis of both experimental and genetic hypertension. Although the importance of the brain RAS in regulating normal and pathophysiological CV responses have been implicated in studies utilizing targeted application of lesions and pharmacological agents, the relative effect on blood pressure (BP) of stimulating central neural and peripheral vascular AT1 receptor remains unclear. Therefore, the purpose of this proposal is to test the hypotheses that 1) the RAS in the brain, through the action of ANG-II at neuronal AT1 receptors localized in several CV control centers, in an important determinant in the regulation of BP, heart rate (HR), sympathetic outflow, and baroreceptor reflex function under normal conditions and in hypertension, 2) CNS responses to ANG-II are differentially mediated by AT1 subtype-A and subtype-B receptors which exhibit differential localization in the brain, and 3) over expression of AT1 receptors in the brain may be involved in the pathogenesis of hypertension. We will test these hypothesis by performing integrative cardiovascular physiology, pharmacology and molecular biology in transgenic and gene-targeted (""""""""knockout"""""""") mice. We will take advantage of AT1A and AT1B deficient mice as genetic tools to examine the CV consequences of the loss of one AT1 receptor subtype versus the other. Moreover, we will combine the use of strong highly-specific promoters to target AT1 receptor expression to neurons in the CNS and to smooth muscle cells (SMC) in the vasculature with the AT1 receptor deficient mice in order to selectively complement (genetically replace) AT1 receptors in a cell-specific fashion. These studies will provide important information on the differential contribution of neuronal and vascular AT1A and AT1B receptors in mediating central CV responses to ANG-II.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL014388-27
Application #
6109369
Study Section
Project Start
1999-01-01
Project End
1999-12-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
27
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Iowa
Department
Type
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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