The long term goal is to define in biochemical and genetic terms the genes which cause hypertension in genetically hypertensive rats. The main focus of the present work is atrial natriuretic factor (ANF) in our inbred strains of Dahl salt-hypertension sensitive (S/JR) and Dahl salt-hypertension resistant (R/JR) rats. Defining the role of ANF in blood pressure regulation of genetically hypertensive rats will bear directly on whether this system can influence blood pressure in human hypertension. Preliminary data suggest that there are two genetic defects in S/JR rats compared to R/JR. S/JR kidneys are hyporesponsive to ANF, and S/JR atria may release inappropriately low amounts of ANF in response to high salt (NaCl) intake. The mechanisms behind these strain differnces will be investigated with the purpose not only of understanding the important physiologic and biochemical mechanisms but also with the goal of defining traits which are appropriate for genetic analysis in the future.
Specific Aims are to: 1. Develop further a radioimmunoassay (RIA) for ANF: Although our present RIA works well on tissue extracts and rat plasma, further validation and characterization of the assay is required. 2. Measure ANF in tissues and plasma: preliminary data show low plasma levels of ANF in S/JR rats fed high salt diet compared to comparably treated R/JR. These observations will be extended in acute and chronic experiments where salt and water intake are varied. 3. Study release of ANF from atria of S/JR and R/JR strains: Release of ANF in vitro in response to agonist-induced and mechanically-induced (pressure and stretch) release will be quantitated. 4. Evaluate renal vascular responses to ANF in S/JR and R/JR strains. 5. Characterize a renal receptor for ANF and compare the properties and numbers of such receptors in S/JR and R/JR rats. 6. Use the techniques of molecular biology to evaluate mRNA levels and gene structure for ANF in S/JR and R/JR rats.
