Vasopressin (AVP) is released in response to both osmotic and nonosmotic stimuli. Nonosmotic-stimulated AVP release occurs in
cardiac failure,
cirrhosis, and pregnancy in response to alterations in arterial circulatory integrity.
Cardiac failure in rats is associated with increased plasma AVP and hypothalamic AVP
mRNA, and in humans, it is associated with
cardiac failure. Plasma AVP concentrations are elevated when measured with a sensitive radioimmunoassay. Urinary concentrations of AVP-responsive
aquaporin-2 water channels are also elevated in
cardiac failure.
V2 receptor antagonists correct the impaired solute-free water excretion seen in rats with low-output cardiac failure and reverse the upregulation of renal
aquaporin-2 water channels. Orally active non-
peptide-selective
V2 receptor antagonists administered to patients with congestive
cardiac failure decrease urinary concentrations of
aquaporin-2, increase solute-free water clearance, and correct the
hyponatremia.
Cirrhosis of the liver results in splanchnic arterial vasodilation and increased vascular capacity, most likely secondary to increased
nitric oxide production. This relative underfilling of the arterial circulation stimulates nonosmotic AVP release with resultant water retention.
Aquaporin-2 gene expression is upregulated in the kidneys of rats with
cirrhosis of the liver. AVP-2 receptor antagonists administered to animals with
cirrhosis reverse the water retention. Human studies using orally active, non-
peptide-selective
V2 receptor antagonists in patients with
cirrhosis are currently underway. Pregnancy is another state of
nitric oxide-mediated arterial vasodilation that is associated with plasma AVP concentrations that are relatively high for the degree of hypoosmolality. Upregulation of the
water channel aquaporin-2 in the renal papillae of pregnant rats has also been demonstrated, and this effect is reversed by administration of a
V2 receptor antagonist.