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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL035642-03
Application #
3349723
Study Section
(SRC)
Project Start
1985-09-30
Project End
1990-09-29
Budget Start
1987-09-30
Budget End
1988-09-29
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Harvard University
Department
Type
Schools of Medicine
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
Shen, Y T; Graham, R M; Vatner, S F (1991) Effects of atrial natriuretic factor on blood flow distribution and vascular resistance in conscious dogs. Am J Physiol 260:H1893-902
Seidman, C E; Schmidt, E V; Seidman, J G (1991) cis-dominance of rat atrial natriuretic factor gene regulatory sequences in transgenic mice. Can J Physiol Pharmacol 69:1486-92
Rosenzweig, A; Halazonetis, T D; Seidman, J G et al. (1991) Proximal regulatory domains of rat atrial natriuretic factor gene. Circulation 84:1256-65
Shen, Y T; Young, M A; Ohanian, J et al. (1990) Atrial natriuretic factor-induced systemic vasoconstriction in conscious dogs, rats, and monkeys. Circ Res 66:647-61
Wildey, G M; Fischman, A J; Margolies, M N et al. (1990) Phosphorylation state of pro-atrial natriuretic factor in rat atrial secretory granules. Endocrinology 127:2839-48
Ohanian, J; Young, M A; Shen, Y T et al. (1989) Natriuretic and diuretic effects of infusion of atrial natriuretic factor in conscious dogs. Am J Physiol 257:F565-73
Lee, R T; Bloch, K D; Pfeffer, J M et al. (1988) Atrial natriuretic factor gene expression in ventricles of rats with spontaneous biventricular hypertrophy. J Clin Invest 81:431-4
Seidman, C E; Wong, D W; Jarcho, J A et al. (1988) Cis-acting sequences that modulate atrial natriuretic factor gene expression. Proc Natl Acad Sci U S A 85:4104-8
Bloch, K D; Zamir, N; Lichtstein, D et al. (1988) Ouabain induces secretion of proatrial natriuretic factor by rat atrial cardiocytes. Am J Physiol 255:E383-7
Fischman, A J; Wildey, G M; Matsueda, G R et al. (1988) Specificity of serine proteases for cleavage sites on proatrial natriuretic factor. Peptides 9:1275-83

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