Characterization of SR 121463A, a highly potent and selective, orally active vasopressin V2 receptor antagonist.

Gal, Claudine Serradeil–Le; Lacour, Colette; Valette, G; Garcia, Georges; Foulon, Loïc; Galindo, G; Bankir, Lise; Pouzet, Brigitte; Guillon, Gilles; Barberis, Claude; Chicot, D; Jard, Serge; Vilain, P.; Garcia, Cyrielle; Marty, E.; Raufaste, Danielle; Brossard, Gabrielle; Nisato, Dino; Maffrand, Jean‐Pierre; Fur, G. Le

doi:10.1172/jci119098

Cited by 237 publications

(158 citation statements)

References 48 publications

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“…Of interest is the effect of a V 2 receptor antagonist to increase urine flow further in the BBDM rats, which supports an earlier observation by Serradeil-Le Gal et al (25). In this regard, plasma oxytocin has been shown to be increased in BB rats, and oxytocin exerts its antidiuretic action via the vasopressin V 2 receptor (26).…”

Section: Discussionsupporting

confidence: 80%

Hyperosmolality In Vivo Upregulates Aquaporin 2 Water Channel and Na-K-2Cl Co-Transporter in Brattleboro Rats

Wang²,

Summer³

et al. 2006

Journal of the American Society of Nephrology

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There are considerable experimental results that indicate that arginine vasopressin (AVP)-independent factors are involved in urinary concentration. This study examined the role of hyperosmolality in vivo to modulate aquaporin 2 (AQP2) and Na-K-2Cl co-transporter (NKCC2), pivotal factors in urinary concentration, in AVP-deficient Brattleboro (BB) rats. Hyperglycemia with associated hyperosmolality occurred in diabetic BB rats (BBDM). Protein abundance of AQP2 increased and was reversed by insulin in the inner medulla (IM; control 100 ؎ 5%; BBDM 146 ؎ 8%; BBDM؉Ins 122 ؎ 9%; P < 0.001) and inner stripe of outer medulla (ISOM; control 100 ؎ 4%; BBDM 123 ؎ 8%; BBDM؉Ins 93 ؎ 6%; P < 0.05). These results were confirmed by immunohistochemistry studies. NKCC2 rose in the ISOM but was not reversed with insulin treatment. For investigation of the role of hyperosmolality in the absence of hyperglycemia on the regulation of the expression of renal AQP and NKCC2, studies were performed with hyperosmolality that was induced by 0.5% NaCl in drinking water in BB rats. Hyperosmolality that was induced by NaCl increased significantly the protein abundance of IM AQP2 (121 ؎ 2 versus 100 ؎ 5%; P < 0.01), ISOM AQP2 (135 ؎ 6 versus 100 ؎ 5%; P < 0.001), cortex plus outer stripe of outer medulla AQP2 (121 ؎ 4 versus 100 ؎ 1%; P < 0.001), ISOM NKCC2 (133 ؎ 1 versus 100 ؎ 4%; P < 0.05), and cortex plus outer stripe of outer medulla NKCC2 (142 ؎ 16 versus 100 ؎ 9%; P < 0.05). In conclusion, hyperosmolality, secondary to either glucose or NaCl, upregulated renal AQP2 and NKCC2 in vivo in BB rats.J Am Soc Nephrol 17: 1657 -1664, 2006 . doi: 10.1681 R enal water excretion is regulated by arginine vasopressin (AVP), which increases the water permeability in the collecting duct (CD) (1,2). Recently, the water channel aquaporin 2 (AQP2) that mediates the water transport in the CD in response to vasopressin was identified (3). It is widely known that AQP2 is the main target for the action of vasopressin to regulate CD water reabsorption and hence body water balance via the V 2 receptor and cAMP pathway (4).There is, however, some in vitro evidence for vasopressinindependent effects on the regulation of water channels. For example, it has been demonstrated that hypertonicity enhances the expression and the stability of AQP1 in the absence of AVP in cultured murine renal medullary cells (5). Hyperosmolality also increased the expression of AQP3 in vitro (6). In recent in vitro studies, a long-term (24 h) increase of extracellular tonicity by addition of NaCl or sucrose increased AQP2 expression via stimulation of AQP2 gene transcription (7). In mouse inner medullary CD mIMCD3 cell lines that were transfected with AQP2 cDNA, hyperosmolality with supplemented NaCl increased the expression of nonglycosylated AQP2 and enhanced the apical membrane insertion of nonglycosylated AQP2 in the absence of AVP. These results indicate that hyperosmolality may play a critical role in the regulation of AQP2 in the CD (8). Taken together, these in vitro studies s...

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Section: Discussionsupporting

confidence: 80%

Hyperosmolality In Vivo Upregulates Aquaporin 2 Water Channel and Na-K-2Cl Co-Transporter in Brattleboro Rats

Wang²,

Summer³

et al. 2006

Journal of the American Society of Nephrology

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“…157 Most existing information refers to this compound, but other nonpeptide, orally active, V 2 receptor antagonists have been described recently, including SR-121463A and VPA-985. [158][159][160] The potency and receptor selectivity of OPC-31260 was evaluated in in vitro receptor binding assays using rat liver plasma membranes for V 1 receptors and kidney plasma membranes for V 2 receptors. 123 show a greater affinity for V 2 receptors and a lower affinity for V 1 receptors than OPC-31260 from several species, including humans.…”

Section: Aquaretic Drugsmentioning

confidence: 99%

Hyponatremia in cirrhosis: From pathogenesis to treatment

et al. 1998

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“…2 A benzazepine derivative named OPC-31260 was the first nonpeptide V2-receptor antagonist, and was introduced in 1992. [10][11][12] Two other compounds, SR-121463A 13 and VPA-985, 14,15 are now available. Compared with OPC-31260, these compounds exhibit a higher affinity and selectivity for V2-receptors, suggesting better efficacy.…”

mentioning

confidence: 99%

Pharmacodynamic effects of a nonpeptide antidiuretic hormone V2 antagonist in cirrhotic patients with ascites

Guyader

Patat²,

Ellis-Grosse³

et al. 2002

Hepatology

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Water retention and dilutional hyponatremia, mainly attributable to an impairment of free water excretion and increased vasopressin activity, are well-documented complications in cirrhotic patients with ascites. VPA-985 is a selective, nonpeptide, orally active, vasopressin-2-receptor antagonist. The aim of this study was to determine the pharmacodynamics, safety, and pharmacokinetics of ascending single doses (25, 50, 100, 200, and 300 mg) in cirrhotic patients with ascites in a randomized, double-blind, placebo-controlled trial. Each dose level was studied in 5 patients (4 active and 1 placebo). After an overnight fast and fluid restriction (continued for 4 hours after dose administration), all patients were given placebo on baseline day and an oral suspension of VPA or placebo on the following day. VPA produced a significant dose-related increase in daily urine output (1,454 ؎ 858 mL to 4,568 ؎ 4,385 mL with VPA 300 mg) and a dose-related decrease in urine osmolality. The free water clearance reached greater than 3 mL/min for doses 100 mg or greater. Simultaneously, significant increases in serum osmolality, sodium, and vasopressin levels were found. There was a significant increase in sodium urine excretion. VPA was rapidly absorbed and maximum serum concentrations were achieved within 1 hour after administration. I n normal individuals, the administration of a water load (20 mL/kg body weight of 5% glucose intravenously or water orally over 45 min) is followed by an increase in the excretion of a hypotonic (Ͻ100 mOsm/ kg) urine flow responsible for an increase in free water clearance (FWC) reaching 6 to 12 mL/min. Cirrhotic patients without ascites have normal water handling. 1 Up to 75% of cirrhotic patients with ascites, however, have moderate reduction (1-6 mL/min) of FWC after a water load. In approximately 30% of cases, the impairment is severe (Ͻ1 mL/min after water load) leading to spontaneous hyponatremia because those patients are unable to excrete regular water intake. 2 Hyponatremia can also be triggered or aggravated by the use of diuretics in about 25% of cases. Pathophysiologic mechanisms leading to water overload are not fully understood, but several factors may be involved, among them: (1) reduced delivery of filtrate to the ascending limb of the loop of Henle, secondary to enhancement of proximal sodium reabsorption and decrease of glomerular filtration rate; (2) reduced renal synthesis of prostaglandins; and (3) increased secretion of antidiuretic hormone. 3 There is some evidence to indicate that increased plasma arginine vasopressin (AVP) concentration plays a major role: a correlation between plasma AVP levels and the magnitude of FWC impairment 4 ; the temporal relationship between impairment of water excretion and vasopressin hypersecretion in rats with experimental cirrhosis; 5 the aquaretic effect of -opioid agonists, which act through inhibition of AVP release

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Characterization of SR 121463A, a highly potent and selective, orally active vasopressin V2 receptor antagonist.

Cited by 237 publications

References 48 publications

Hyperosmolality In Vivo Upregulates Aquaporin 2 Water Channel and Na-K-2Cl Co-Transporter in Brattleboro Rats

Hyperosmolality In Vivo Upregulates Aquaporin 2 Water Channel and Na-K-2Cl Co-Transporter in Brattleboro Rats

Hyponatremia in cirrhosis: From pathogenesis to treatment

Pharmacodynamic effects of a nonpeptide antidiuretic hormone V2 antagonist in cirrhotic patients with ascites

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