GENETICS OF ATRIAL NATRIURETIC FACTOR AND HYPERTENSION

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Atrial natriuretic factor (ANF) is a recently discovered peptide stored in specific granules within the atrial myocyte that has potent natriuretic and vasorelaxant properties. Although considerable progress has been made in elucidating its primary structure and in isolating and characterizing its gene, the significance of ANF as a humoral factor in maintaining cardiovascular homeostasis, particularly in relation to volume and blood pressure control, is virtually unknown. It is the major aim of this proposal to define this role. The approach is multidisciplinary and will utilize methods from the fields of molecular biology, immunochemistry and phsyiology. Transcriptional and translational control mechanisms will be investigated utilizing CDNA probes and immunoprecipitation procedures to quantitate ANF production in cultured atrial cardiocytes in response to specific stimuli. Immunochemical techniques will be developed to measure ANF levels in plasma and to determine the structure of the stored, secreted and circulating forms. Intact animal studies, in particular the conscious instrumented dog, will allow us to relate changes in ANF synthesis (i.e. transcriptional and translational regulation) and release to specific physiological manipulations, including the development of perinephritic hypertension, as well as to define the neural, vascular and humoral factors that regulate these processes. Similarly, stu7dies in humans will be initiated to define the role of ANF in maintaining volume and pressure homeostasis. These studies will also form the basis for identifying potential diseases that ;may represent abnormalities in the genetic regulation of ANF production. In particular, the method of restriction fragment length analysis to define polymorphisms in the ANF gene or in its vicinity will be utilized to identify potential linkage with particular disease states where such an abnormality might be predicted, such as Bartter's and Gordon's syndromes. These techniques will also be extended to test the hypothesis that a genetic abnormality in ANF expression may be involved in the etiology of certain forms of hypertension.