[Vasopressin V2 receptor antagonists: pharmacological properties and clinical implications]

Vasopressin, or anti-diuretic hormone, is a peptide hormone that plays an important role in the regulation of extracellular volume and its osmolarity. Increased plasma osmolarity and hypovolemia are the principal physiological stimuli for vasopressin release. The biological effects of vasopressin on its target organs are mediated by two receptors: V1 and V2. V2 is localized to renal tissue and its activation leads to upregulation of aquaporin-2 in the collecting duct allowing the reabsorption of large volumes of water. In contrast, V1 is expressed mainly in blood vessel walls, and its activation results in vascoconstriction. Besides the physiological importance of the vasopressin system, it also plays a crucial role in the pathogenesis of various diseases, including congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone secretion. These clinical syndromes are characterized by enhanced plasma levels of vasopressin, which correlate with the severity of the disease and largely contribute to the development of edema and hyponatremia. Great efforts have been invested in attempting to develop selective and long lasting vasopressin antagonists. However, general medicine and particularly nephrology, suffered from the absence of non-peptide vasopressin blockers that could be taken orally. The last few years have witnessed the development of numerous selective vasopressin antagonists with high bioavailability and long half-lives. Administration of these antagonists to patients with congestive heart failure, cirrhosis, and syndrome of inappropriate antidiuretic hormone secretion substantially enhanced free water excretion and moderately increased serum sodium concentrations. No side effects, except for mild increased thirst sensation, were observed. The present review focuses on the recent developments in vasopressin research, with special emphasize on the development of selective non-peptide antagonists and their clinical use.