BIOCHEMISTRY AND GENETICS OF HYPERTENSION

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My longterm objective is to define in biochemical and genetic terms the genes which influence blood pressure and to evaluate the interactive effects of these genes on blood pressure. The grant has three components: a) studies on atrial natriuretic factor (ANF); b) cosegregation analysis; c) studies on genomic DNA. Studies on ANF will investigate possible reasons why the kidneys of inbred Dahl salt-sensitive (S/JR) rats are hyporesponsive to ANF compared to inbred Dahl salt-sensitive (S/JR) rats hyporesponsive to ANF compared to inbred Dahl salt-resistant (R/JR) rats. ANF receptors and cellular post-receptor events will be characterized in Dahl rats. Renal responses to ANF at the physiological level of membrane transport, renal functional tests and vasodilatory responses will be evaluated in Dahl rats. S/JR rats also have higher atrial ANF content then R/JR, and this is probably genetically mediated. ANF release from heart-lung preparations under varying conditions of preload, after load and extracellular (Na) will determine if there is any abnormality of ANF release in Dahl rats. mRNA for ANF from atria of Dahl rats will be quantitated under a variety of stimuli to determine if there is any abnormality of ANF regulation at the mRNA step. Cosegregation analysis will be used to determine if observed marked differences in adrenal renin in S/JR vs R/JR rats are causally related to blood pressure differences. Also the interactions on blood pressure of specific genes known to influence blood pressure in the rat (Hyp-l, Hyp-2, Es 4), will be determined in genetic experiments. Lastly, genes that code for molecules of interest in hypertension (ANF, cytochrome P450 11 beta/18, calcitonin, renin, angiotensin, calcitonin-gene-related peptide, neuropetide Y) will be compared for mutations at the genomic DNA level in S/JR and R/JR rats. These known genes will be obtained from genomic DNA libraries of S/JR and R/JR rats using oligonucleotide probes, and the genes will be compared between strains by cross hybridization techniques, sequence-determined gel electrophoresis, restriction fragment length polymorphisms, and base sequencing. Any DNA polymorphisms found between S/JR and S/JR strains will be tested for a causal relationship to the blood pressure differences between strains by cosegregation analysis.