Aquaretic and hormonal effects of a vasopressin V2 receptor antagonist after acute and long-term treatment in rats

Lacour, Colette; Galindo, G; Canals, Françoise; Segondy, Danielle; Cazaubon, Catherine; Gal, Claudine Serradeil–Le; Roccon, Alain; Nisato, Dino

doi:10.1016/s0014-2999(00)00088-1

Cited by 13 publications

(10 citation statements)

References 22 publications

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“…31 Although not significantly dose related, we found an increase in urine sodium levels. This effect also has been reported in experimental models of rats with or without cirrhosis 26,32 and the exact mechanisms remain unclear. Plasma AVP levels increased, probably because of the osmotic release induced by the increase in plasma osmolality.…”

Section: Discussionmentioning

confidence: 61%

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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Section: Discussionmentioning

confidence: 61%

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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“…Compounds were screened against DDAVP-induced cremasteric vasorelaxation of previously U46619-generated vasoconstriction. DDAVP-induced cremasteric vasorelaxation was confirmed as V2R-dependent, as established V2R-selective competitive antagonist SR121463 (42,68) abolished the vasorelaxation (Fig. 2A); the V1aR selective antagonist SR49059 was ineffective ( Fig.…”

Section: Screening Of Peptides Derived From Extracellular Juxtamembramentioning

confidence: 76%

VRQ397 (CRAVKY): a novel noncompetitive V2 receptor antagonist

Řihakova

Quiniou

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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Vasopressin type 2 receptor (V2R) exhibits mostly important properties for hydroosmotic equilibrium and, to a lesser extent, on vasomotricity. Drugs currently acting on this receptor are analogs of the natural neuropeptide, arginine vasopressin (AVP), and hence are competitive ligands. Peptides that reproduce specific sequences of a given receptor have lately been reported to interfere with its action, and if such molecules arise from regions remote from the binding site they would be anticipated to exhibit noncompetitive antagonism, but this has yet to be shown for V2R. Six peptides reproducing juxtamembranous regions of V2R were designed and screened; the most effective peptide, cravky (labeled VRQ397), was characterized. VRQ397 was potent (IC(50) = 0.69 +/- 0.25 nM) and fully effective in inhibiting V2R-dependent physiological function, specifically desmopressin-L-desamino-8-arginine-vasopressin (DDAVP)-induced cremasteric vasorelaxation; this physiological functional assay was utilized to avoid overlooking interference of specific signaling events. A dose-response profile revealed a noncompetitive property of VRQ397; correspondingly, VRQ397 bound specifically to V2R-expressing cells could not displace its natural ligand, AVP, but modulated AVP binding kinetics (dissociation rate). Specificity of VRQ397 was further confirmed by its inability to bind to homologous V1 and oxytocin receptors and its inefficacy to alter responses to stimulation of these receptors. VRQ397 exhibited pharmacological permissiveness on V2R-induced signals, as it inhibited DDAVP-induced PGI(2) generation but not that of cAMP or recruitment of beta-arrestin2. Consistent with in vitro and ex vivo effects as a V2R antagonist, VRQ397 displayed anticipated in vivo aquaretic efficacy. We hereby describe the discovery of a first potent noncompetitive antagonist of V2R, which exhibits functional selectivity, in line with properties of a negative allosteric modulator.

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“…In well hydrated conscious rats, V 2 receptor antagonism increases urine flow and decrease urine osmolality [43,45,46]. Clinical studies ( Table 2) have confirmed these effects in humans.…”

Section: Selective V 2 Receptor Antagonismmentioning

confidence: 99%

Therapeutic role of vasopressin receptor antagonism in patients with liver cirrhosis

et al. 2003

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Vasopressin, or antidiuretic hormone, is a peptide hormone that is released from the posterior pituitary gland in response to changes in blood pressure and plasma osmolality. The main pathophysiological states associated with high plasma vasopressin concentrations are cirrhosis, cardiac failure and syndrome of inappropriate antidiuretic hormone (SIADH) secretion. Pharmacological treatments for disorders of excess vasopressin secretion have been limited. However, oral bio-available selective and non-selective V(1) and V(2) receptor antagonists have recently become available for clinical use. Water retention in cirrhosis is a common problem, leading to ascites, peripheral oedema and hyponatraemia. Raised plasma vasopressin concentrations and decreased delivery of glomerular filtrate are believed to be the most important factors in the development of water retention. V(2) receptor antagonists are aquaretic agents that promote water excretion and improve hyponatraemia. Their potential role in cirrhosis has been examined in a number of recent studies that have shown increased free water clearance and serum sodium concentrations with few adverse effects. V(2) receptor antagonists represent a novel and promising new class of agent that may have major clinical utility in the treatment of patients with liver cirrhosis.

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Aquaretic and hormonal effects of a vasopressin V2 receptor antagonist after acute and long-term treatment in rats

Cited by 13 publications

References 22 publications

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

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

VRQ397 (CRAVKY): a novel noncompetitive V2 receptor antagonist

Therapeutic role of vasopressin receptor antagonism in patients with liver cirrhosis

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