The work outlined in this project builds upon our demonstrations that receptor density, affinity and subtype profile are altered in the brain of rats with genetic hypertension [spontaneously hypertensive rats (SHR)] or after ICV infusion of Ang peptides. We will attempt to determine the potential mechanisms for these changes in receptors by studies in Ren-2 transgenic (TG) rats, a genetic model of hypertension associated with elevated brain and adrenal Ang peptides. In both TG rats and SHR, receptor binding is lower in the dorsomedial medulla of rats treated chronically with the converting enzyme inhibitor lisinopril. The reduction in binding is not related solely to the reduction in pressure that occurs, but may be dependent upon central changes in Ang peptide levels. Thus, the pattern of distribution and density of Ang receptors, binding affinity, subtype profile an ligand selectivity [i.e., for Ang- (1-7), Ang-(2-8)], and AT1 receptor mRNA will be determined initially and after treatments that control the level of arterial pressure, change the level of specific Ang peptides, or both. Correlations will be made with peptide levels in plasma and tissues determined in Projects 1 and 6 during the development of the hypertension, and during treatment with agents that interfere with the action of the renin-angiotensin system (RAS). The second major goal is to establish whether functional relationships exist between release of specific transmitters and prostaglandins in isolated brain slices and the observed changes in receptors. These studies in isolated systems in vitro using relatively intact tissues (brain slices) will complement studies investigating signal transduction mechanisms in isolated cell system in Project 3. In addition, alterations in receptors in receptor density or profile and any parallel changes in responsiveness observed in vitro, will also complement studies of Ang peptide physiology and function in intact animals in Project 1, and 4-6.
Showing the most recent 10 out of 309 publications
