The atrial natriuretic factors represent a family of peptides with potent vasorelaxant and diuretic activities. These peptides are synthesized at a high level in the cardiac atrium and may play important roles in regulating systemic blood pressure and fluid and electrolyte homeostasis. As such, disorders of their regulation or expression could play important roles in the genesis of human diseases (e.g. systemic hypertension). The proposed studies are designed to learn more about the regulation of plasma and tissue ANF levels, the expression of the ANF genes in cardiac and extracardiac tissues and the role of ANF in animal and human hypertension. Preliminary studies suggest that the ANF gene is expressed not only in the atrium, but also in the ventricle, lung, pituitary, hypothalamus and aortic arch. These data raise the possibility that expression of extra-atrial ANF could act in an endocrine, paraendocrine or local role to regulate cardiovascular function. ANF mRNA levels are also regulated by glucocorticoids in atrium, ventricle, lung and pituitary, and are increased in dogs which have 'escaped' from the Na+ retaining effects of mineralocorticoid hormones. In the proposed studies it is hoped to: define the extent of ANF expression in a wider variety of tissues at the RNA and protein level; define the in vivo effects of steroid hormones in greater detail; determine the effects of perturbations of the renin-angiotensin system, antidiuretic hormone and salt and water balance on ANF gene expression; compare ANF gene expression in normal and hypertensive rats; establish in vitro sysems to study ANF gene expression; use gene transfer techniques to determine the molecular mechanisms and DNA structures in the ANF gene that are involved in its regulation and tissue specific expression; and, search for polymorphisms in the ANF gene of patients with hypertension, which might be used as markers of genetic susceptibility to this disorder. These studies should be helpful in furthering the understanding of the potential importance of this hormone as a regulator of cardiovascular function and in the pathogenesis of human hypertension.
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