The recent development of genetic mouse models presenting life-long alterations in expression of the genes for
atrial natriuretic peptide (
ANP) or its receptors (NPR-A, NPR-C) has uncovered a physiological role of this
hormone in chronic blood pressure homeostasis. Transgenic mice overexpressing a
transthyretin-
ANP fusion gene are hypotensive relative to the nontransgenic littermates, whereas mice harboring functional disruptions of the
ANP or NPR-A genes are hypertensive compared with their respective wild-type counterparts. 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 conditions of normal dietary
salt consumption, the hypotensive action of
ANP is dissociated from the natriuretic activity of the
hormone. However, during elevated dietary
salt intake,
ANP-mediated antagonism of the renin-angiotensin system is essential for maintenance of blood pressure constancy, inasmuch as the
ANP gene "knockout" mice (
ANP -/-) develop a
salt-sensitive component of
hypertension in association with failure to adequately downregulate 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.