ANP in regulation of arterial pressure and fluid-electrolyte balance: lessons from genetic mouse models

The recent development of genetic mouse models presenting life-long alterat ions in expression of the genes for atrial natriuretic peptide (ANP) or its receptors (NPR-A, NPR-C) has uncovered a physiological role of this hormon e in chronic blood pressure homeostasis. Transgenic mice overexpressing a t ransthyretin-ANP fusion gene are hypotensive relative to the nontransgenic littermates, whereas mice harboring functional disruptions of the ANP or NP R-A genes are hypertensive compared with their respective wild-type counter parts. The chronic hypotensive action of ANP is determined by vasodilation of the resistance vasculature, which is probably mediated by attenuation of vascular sympathetic tone at one or several prejunctional sites. Under con ditions of normal dietary salt consumption, the hypotensive action of ANP i s dissociated from the natriuretic activity of the hormone. However, during elevated dietary salt intake, ANP-mediated antagonism of the renin-angiote nsin system is essential for maintenance of blood pressure constancy, inasm uch as the ANP gene "knockout" mice (ANP -/-) develop a salt-sensitive comp onent of hypertension in association with failure to adequately downregulat e plasma renin activity. These findings imply that genetic deficiencies in ANP or natriuretic receptor activity may be underlying causative factors in the etiology of salt-sensitive variants of hypertensive disease and other sodium-retaining disorders, such as congestive heart failure and cirrhosis.