VASOPRESSIN RELEASE, WATER CHANNELS, AND VASOPRESSIN ANTAGONISM IN CARDIAC-FAILURE, CIRRHOSIS, AND PREGNANCY

Vasopressin (AVP) is released in response to both osmotic and nonosmot ic stimuli. Nonosmotic-stimulated AVP release occurs in cardiac failur e, cirrhosis, and pregnancy in response to alterations in arterial cir culatory integrity. Cardiac failure in rats is associated with increas ed plasma AVP and hypothalamic AVP mRNA, and in humans, it is associat ed with cardiac failure. Plasma AVP concentrations are elevated when m easured with a sensitive radioimmunoassay. Urinary concentrations of A VP-responsive aquaporin-2 water channels are also elevated in cardiac failure. V2 receptor antagonists correct the impaired solute-free wate r excretion seen in rats with low-output cardiac failure and reverse t he upregulation of renal aquaporin-2 water channels. Orally active non -peptide-selective V2 receptor antagonists administered to patients wi th congestive cardiac failure decrease urinary concentrations of aquap orin-2, increase solute-free water clearance, and correct the hyponatr emia. Cirrhosis of the liver results in splanchnic arterial vasodilati on and increased vascular capacity, most likely secondary to increased nitric oxide production. This relative underfilling of the arterial c irculation stimulates nonosmotic AVP release with resultant water rete ntion. Aquaporin-2 gene expression is upregulated in the kidneys of ra ts with cirrhosis of the liver. AVP-2 receptor antagonists administere d 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 associate d with plasma AVP concentrations that are relatively high for the degr ee of hypoosmolality. Upregulation of the water channel aquaporin-2 in the renal papillae of pregnant rats has also been demonstrated, and t his effect is reversed by administration of a V2 receptor antagonist.