Molecular Pharmacology of Human Vasopressin Receptors

Thibonnier, Marc; Conarty, Doreen M.; Preston, Judith A.; Wilkins, Pamela L.; Berti‐Mattera, Liliana N.; Mattera, Rafael

doi:10.1007/978-1-4615-4871-3_34

Cited by 143 publications

(117 citation statements)

References 52 publications

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“…No significant effect on blood pressure was observed, confirming previous reports that VPA-985 has little or no effect on V1 receptors. 14,15,34 Therefore, these results and the results of other doubleblind clinical trials 29,30 in hyponatremic patients show that VPA-985 may correct the impairment in water excretion owing to nonosmotic vasopressin stimulation observed in patients with liver cirrhosis with ascites, and the dilutional hyponatremia that may occur.…”

Section: Discussionmentioning

confidence: 62%

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: 62%

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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“…The results obtained are reported in Table I. The observed high affinities for AVP, for the V1a agonist Phe 2 Orn 8 VT, and the three V1a selective antagonists together with the observed low affinities for oxytocin, for the oxytocin selective agonist Thr 4 Gly 7 OT, and the V2 selective agonist dDAVP, clearly indicate that the receptor expressed in CHO cells has the expected pharmacological profile of the human V1a receptor (23). Furthermore, the expressed receptor is functionally coupled to phospholipase C. Stimulation of transfected CHO cells by vasopressin induced a maximum 6 -8-fold increase in inositol phosphate accumulation with an apparent K act value close to the measured K d value for vasopressin binding (see Table I).…”

Section: Binding and Coupling Properties Of The Wild-type Receptor-mentioning

confidence: 77%

“…The human V1a receptor cDNA was a generous gift of Dr. M. Thibonnier (23). A stretch of nucleotides coding for a 10-amino acid epitope (EQKLISEEDL) of the human c-Myc protein (24) was inserted after the initiating Met codon of the human V1a vasopressin receptor cDNA using oligonucleotide-directed mutagenesis.…”

Section: Construction Of Epitope-tagged Human V1a Vasopressin Receptor-mentioning

confidence: 99%

Mapping Peptide-binding Domains of the Human V1a Vasopressin Receptor with a Photoactivatable Linear Peptide Antagonist

Phalipou

Cotte

Carnazzi

et al. 1997

Journal of Biological Chemistry

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The study of antagonist-binding domains of the human V1a vasopressin receptor was performed using a radioiodinated photoreactive peptide antagonist. This ligand displayed a high affinity for the receptor expressed in Chinese hamster ovary cell membranes, and specifically labeled two protein bands with apparent molecular mass at 85-90 and 46 kDa. Our results clearly show that the V1a receptor is degraded during incubation with the ligand and that the 46-kDa species is probably the result of the 85-90-kDa species proteolytic cleavage. Truncation of the receptor was then confirmed by deglycosylation with N-glycosidase F. A monoclonal antibody directed against a c-Myc epitope added at the receptor NH 2 terminus allowed immunoprecipitation of the 85-90-kDa photolabeled species. The 46-kDa photolabeled protein never immunoprecipitated, indicating that the truncated form of the receptor lacks the NH 2 terminus region. To localize photolabeled domains of the receptor, the 46-kDa protein was cleaved with V8 and/or Lys-C endoproteinases. The identity of the smallest photolabeled fragment, observed at approximately 6 kDa, was then confirmed by mutation of the potential V8 cleavage sites. Our results indicate that covalent labeling of the vasopressin V1a receptor with the photoreactive antagonist occurs in a region including transmembrane domain VII (residues Asn 327 -Lys 370 ).Neurohypophysial hormones, arginine-vasopressin (AVP) 1 and oxytocin, exert a wide range of physiological effects through binding to specific membrane receptors belonging to the G protein-coupled receptor (GPCR) superfamily. To date, three AVP receptor subtypes and one oxytocin receptor have been pharmacologically and functionally described (1). V1a, V1b, and oxytocin receptors activate phospholipase C, resulting in the production of inositol 1,4,5-trisphosphate and diacylglycerol, mobilization of intracellular calcium and activation of protein kinase C. V2 receptors stimulate adenylyl cyclase, resulting in the accumulation of cyclic AMP and activation of protein kinase A. All receptor subtypes from several mammalian species have been recently cloned (2-5), as well as closely related receptors from bony fishes and invertebrates (6, 7).Analysis of the primary sequence of these receptors suggests that they possess the same general architecture with seven transmembrane helices as other well characterized G proteincoupled receptors. Moreover, the comparison of their amino acid sequence reveals significant homology within the putative transmembrane regions (TM) and within the first and second extracellular loops as well. The natural ligands for the receptors of the AVP/oxytocin family are also closely structurally related. All are nonapeptides composed of a 6-amino acid disulfide-linked ring and a COOH terminus tripeptide.Peptides of the AVP/oxytocin series were subjected to an extensive analysis of structure-activity relationships. These studies (for review, see Refs. 8 -11) led to the production of a profusion of valuable pharmacological probes for asse...

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“…The 3 known subtypes differ in localization and signal transduction mechanisms. 103 The AVP V 1a (V 1a R) and V 1b (V 1b R) receptors are Gq-coupled receptors that activate phospholipase C and increase cytosolic free calcium; the physiologic effects caused by activation depend primarily on the localization of the receptors and include vasoconstriction (V 1a R), platelet aggregation (V 1a R), ionotropic stimulation and myocardial protein synthesis (V 1a R), and pituitary ACTH secretion (V 1b R). AVP V 2 receptors (V 2 R) are found on the principal cells of the renal collecting tubules and vascular endothelium, where they mediate the antidiuretic effects of AVP and stimulate release of von Willebrand factor and factor 8, respectively.…”

Section: Vasopressin Receptor Antagonistsmentioning

confidence: 99%

Hyponatremia Treatment Guidelines 2007: Expert Panel Recommendations

Verbalis

Goldsmith

Greenberg

et al. 2007

The American Journal of Medicine

523

498

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Although hyponatremia is a common, usually mild, and relatively asymptomatic disorder of electrolytes, acute severe hyponatremia can cause substantial morbidity and mortality, particularly in patients with concomitant disease. In addition, overly rapid correction of chronic hyponatremia can cause severe neurologic deficits and death, and optimal treatment strategies for such cases are not established. Hyponatremia is the most common disorder of electrolytes encountered in clinical practice, occurring in up to 15% to 30% of both acutely and chronically hospitalized patients. 1 Although most cases are mild and relatively asymptomatic, hyponatremia is important clinically because: (1) acute severe hyponatremia can cause substantial morbidity and mortality; (2) mortality is higher in patients with hyponatremia who have a wide range of underlying diseases; and (3) overly rapid correction of chronic hyponatremia can cause severe neurologic deficits and death.Despite knowledge of hyponatremia since the mid-20th century, this common disorder remains incompletely understood in many basic areas because of its association with a plethora of underlying disease states, and its multiple etiologies with differing pathophysiologic mechanisms. 2 Optimal treatment strategies have not been well defined, both for these reasons and because of marked differences in symptomatology and clinical outcomes based on the acuteness or chronicity of the hyponatremia. 3 Vasopressin receptor antagonists have long been anticipated as a more effective method to treat hyponatremia by virtue of their unique aquaretic effect to selectively increase solute-free water excretion by the kidneys. 4 The recent approval of the first such agent, conivaptan, for clinical use by the US Food and Drug Administration (FDA) heralds the beginning of a new era in the management of hyponatremic disorders. However, effective therapy with these agents will require intelligent guidelines for their use. To this end, a panel of experts in hyponatremia convened to review current therapies for hyponatremia and to evaluate the situations in which aquaretic agents should be considered as alternatives or supplements to accepted current therapies. This review is a summary of the conclusions of this panel.

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Molecular Pharmacology of Human Vasopressin Receptors

Cited by 143 publications

References 52 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

Mapping Peptide-binding Domains of the Human V1a Vasopressin Receptor with a Photoactivatable Linear Peptide Antagonist

Hyponatremia Treatment Guidelines 2007: Expert Panel Recommendations

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