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Figure 1. The vasopressin V2 receptor, vasopressin and a nonpeptide vasopressin-receptor inhibitor (OPC-21268). Molecular modeling of antagonist activity of vaptans. The proposed mechanism is that the vaptans penetrate deeper and more selectively into the binding pocket of the vasopressin receptor type 2 than native vasopressin without activating it, thereby exerting an antagonistic effect. Permission to use this figure was provided by Dr Menachem Shoham.
(Figure omitted. See article PDF.)
Figure 2. Proposed model for high vasopressin levels in heart failure stimulating the V1a and V2 receptors and contributing to its pathophysiology.
(Figure omitted. See article PDF.)
Figure 3. Effect of tolvaptan on serum sodium concentration in SALT-1 and SALT-2 trials. Comparison of mean serum sodium concentrations according to the day of patient visit in patients with HN owing to SIADH, liver cirrhosis or congestive heart failure receiving either tolvaptan (circles) or placebo (squares). Asterisks (p < 0.001) and daggers (p < 0.01) indicate significant differences. SALT-1 and SALT-2 refer to Study of Ascending Levels of Tolvaptan in HN 1 and 2, two identical Phase III randomized controlled trials in the USA (SALT-1) and Europe (SALT-2).
(A) The results of all patients. (B) The results of those with marked HN (baseline serum sodium between 125 and 127 mmol/l). (C) The results of those with mild HN (baseline serum sodium ∼132 mmol/l). Tolvaptan was given orally for 30 days, followed by a 7-day observation period. HN: Hyponatremia; SALT: Study of Ascending Levels of Tolvaptan; SIADH: Syndrome of inappropriate antidiuretic hormone secretion. Reprinted with permission from [33] © 2006 Massachusetts Medical Society. All rights reserved.
(Figure omitted. See article PDF.)
Vasopressin-receptor antagonists, also called 'vaptans', represent a novel class of therapeutic agents, of which some have recently been approved for clinical use. Three types of vasopressin receptors are present in humans, including the V1a, V1b and V2 receptors.
Antagonists targeting one or more of these receptors have been developed for treating a wide variety of disorders. The focus of this article will be on the selective V2- and combined V1a/V2-receptor antagonists, which have primarily been developed for the treatment of hyponatremia in heart failure, liver cirrhosis or the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Their characteristics and current status is summarized in Table 1. V1a-receptor antagonists...