Receptor binding of oxytocin and vasopressin antagonists and inhibitory effects on isolated myometrium from preterm and term pregnant women

Åkerlund, Mats; Bossmar, Thomas; Brouard, R; Kostrzewska, Anna; Laudański, T; Lemancewicz, Adam; Gal, Claudine Secradeil‐Le; Steinwall, Margareta

doi:10.1111/j.1471-0528.1999.tb08112.x

Cited by 110 publications

(106 citation statements)

References 19 publications

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“…We used SR49059, a V1a receptor antagonist that was tested previously in normal volunteers and patients with putative vasopressin excess-related disorders (21)(22)(23)(24). In addition, in vitro studies were done to rescue plasma membrane and signaling of a number of mutant V2 receptors with SR49059 and YM087 (Conivaptan), a mixed V1-V2 antagonist (25)(26)(27)(28)(29).…”

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confidence: 99%

Pharmacologic Chaperones as a Potential Treatment for X-Linked Nephrogenic Diabetes Insipidus

Bernier¹,

Morello²,

Zarruk³

et al. 2006

Journal of the American Society of Nephrology

215

183

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In many mendelian diseases, some mutations result in the synthesis of misfolded proteins that cannot reach a transportcompetent conformation. In X-linked nephrogenic diabetes insipidus, most of the mutant vasopressin 2 (V2) receptors are trapped in the endoplasmic reticulum and degraded. They are unable to reach the plasma membrane and promote water reabsorption through the principal cells of the collecting ducts. Herein is reported two types of experiments: In vivo studies to assess clinically a short-term treatment with a nonpeptide V1a receptor antagonist (SR49059) and in vitro studies in cultured cell systems. In patients, SR49059 decreased 24-h urine volume (11.9 ؎ 2.3 to 8.2 ؎ 2.0 L; P ‫؍‬ 0.005) and water intake (10.7 ؎ 1.9 to 7.2 ؎ 1.6 L; P < 0.05). Maximum increase in urine osmolality was observed on day 3 (98 ؎ 22 to 170 ؎ 52 mOsm/kg; P ‫؍‬ 0.05). Sodium, potassium, and creatinine excretions and plasma sodium were constant throughout the study. A lthough the activities of the protein synthesis quality control systems are generally advantageous to the cell, on occasion this stringent monitoring process can lead to intracellular retention of salvageable proteins. In recent years, its has been observed that a group of diseases stem from mutations that promote such retention and are collectively referred to as conformational or protein-misfolding diseases (1,2). Nephrogenic diabetes insipidus (NDI) (3,4), which is characterized by a loss of arginine vasopressin (AVP)-mediated antidiuresis, is one of these diseases. In congenital NDI that results from mutations in the AVPR2 gene that encodes the V2 receptor, most missense mutations are misfolded, trapped in the endoplasmic reticulum, and unable to reach the basolateral cell surface to engage the circulating antidiuretic hormone, AVP (5-14).The natural history of untreated X-linked NDI includes hypernatremia, hyperthermia, mental retardation, and repeated episodes of dehydration in early infancy (15,16). In five new patients who were younger than 1 year and were from North America and in whom we provided molecular testing over the past 12 mo, plasma sodium was in every case Ͼ155 mEq/L at the time of diagnosis. We and others initially thought that close monitoring of infants whose AVPR2 mutations were diagnosed pre-or perinatally not only would prevent episodes of dehydration but also would permit close to normal growth and development. Although a low-sodium diet and distal tubule diuretics prescribed to these patients may achieve a 20 to 30% decrease in urine output (17), the low-sodium diet is difficult to follow, and affected children continue to drink large amounts of water. As a result of a physiologic gastroesophageal reflux and to the large amount of water in their stomach, these children often vomit, and, as a consequence, their nutritional intake is not optimal. There is a need, therefore, for a safe further reduction in urine output. We recently used pharmacologic compounds to rescue misfolded mutant V2 receptors by demonstrating in cultured cells t...

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mentioning

confidence: 99%

Pharmacologic Chaperones as a Potential Treatment for X-Linked Nephrogenic Diabetes Insipidus

Bernier¹,

Morello²,

Zarruk³

et al. 2006

Journal of the American Society of Nephrology

215

183

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“…Sequence alignment shows that the binding sites of the Oxtr and Avprs are highly conserved, with specific amino acids within the predicted binding pocket providing ligand selectivity (14)(15)(16). The respective ligands Oxt and Avp also are homologous nonapeptides, differing in only two amino acids, and are known to interact with the other's receptor with different affinities (17).…”

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confidence: 99%

Functions of vasopressin and oxytocin in bone mass regulation

Sun

Tamma

Yuen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Prior studies show that oxytocin (Oxt) and vasopressin (Avp) have opposing actions on the skeleton exerted through high-affinity G protein-coupled receptors. We explored whether Avp and Oxtr can share their receptors in the regulation of bone formation by osteoblasts. We show that the Avp receptor 1α (Avpr1α) and the Oxt receptor (Oxtr) have opposing effects on bone mass: Oxtr −/− mice have osteopenia, and Avpr1α −/− mice display a high bone mass phenotype. More notably, this high bone mass phenotype is reversed by the deletion of Oxtr in Oxtr −/− :Avpr1α −/− doublemutant mice. However, although Oxtr is not indispensable for Avp action in inhibiting osteoblastogenesis and gene expression, Avpstimulated gene expression is inhibited when the Oxtr is deleted in Avpr1α −/− cells. In contrast, Oxt does not interact with Avprs in vivo in a model of lactation-induced bone loss in which Oxt levels are high. Immunofluorescence microscopy of isolated nucleoplasts and Western blotting and MALDI-TOF of nuclear extracts show that Avp triggers Avpr1α localization to the nucleus. Finally, a specific Avpr2 inhibitor, tolvaptan, does not affect bone formation or bone mass, suggesting that Avpr2, which primarily functions in the kidney, does not have a significant role in bone remodeling.O ver the past decade, we have described direct actions of anterior and posterior pituitary hormones on the skeleton (1-8). We have shown that these actions are exerted via G protein-coupled receptors resident on both osteoblasts and osteoclasts. We also find that the skeleton is highly sensitive to the action of posterior pituitary hormones; for example, mice haploinsufficient in oxytocin (Oxt) have osteopenic bones, but lactation is normal; lactation is impaired only in Oxt −/− mice (2). Likewise, Tshr haploinsufficient mice are completely euthyroid with normal thyroid follicles but display significant osteopenia (4). The exquisite sensitivity of the skeleton to pituitary hormones comes as no surprise, considering that the pituitary gland and the skeleton are both evolutionarily more primitive than target endocrine organs (7).Apart from the known actions of growth hormone on the skeleton, Tsh, Fsh, Acth, Oxt, and vasopressin (Avp) have all been shown to regulate the formation and/or function of both osteoblasts and osteoclasts and thus to control bone remodeling in vivo (2-4, 6-8). The two neurohypophyseal hormones Oxt and Avp have opposing functions (2, 3). Oxt stimulates and Avp inhibits osteoblast formation. Consequently, the genetic deletion of the Oxt receptor (Oxtr) and Avp receptor 1α (Avpr1α) yields opposing phenotypes, notably osteopenia in Oxtr −/− mice and high bone mass in Avpr1α −/− mice (2, 3). These findings may explain the rapid recovery of bone loss at weaning when plasma Oxt levels are high (9) and also the profound loss of bone noted in chronic hyponatremic states, such as the syndrome of inappropriate antidiuretic hormone secretion (SIADH), in which serum Avp levels are elevated (3).We find high levels of Oxtr expression on ...

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“…The experimental procedure used for in vitro recordings was described in detail recently 6 . In short, at the caesarean section, a myometrial tissue sample of 7 Â 7 Â 15 mm was excised from the upper rim of the transverse incision of the isthmic part of the uterus.…”

Section: Methodsmentioning

confidence: 99%

“…The analogue 1-deamino-2-D-Tyr(OEt)-4-Thr-8-Orn-oxytocin ¼ atosiban (Ferring Pharmaceuticals, Copenhagen, Denmark) was shown to have a high affinity to both receptors 6 , and to inhibit the uterine actions of the peptides in animal experiments and in the human in vitro and in vivo 7 -10 . This analogue was also shown to reduce the contraction rate in preterm labour 11,12 and is now registered in Europe on the indication of delaying imminent preterm birth (TRACTOCILE, Ferring).…”

Section: Introductionmentioning

confidence: 99%

FE 200 440: a selective oxytocin antagonist on the term-pregnant human uterus

Nilsson

2003

BJOG: An International Journal of Obstetrics and Gynaecology

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Objective To compare a newly developed oxytocin antagonist, FE 200 440, with atosiban and ANTAG III, as to potency and selectivity of inhibitory effects on oxytocin-and vasopressin-induced myometrial responses. FE 200 440 has high affinity for the human cloned oxytocin receptor, approximately 300-fold that for the vasopressin V 1a receptor, whereas atosiban binds well to both receptors. Design In vitro study of human myometrial contractility.Setting The Research Laboratory of the Department of Obstetrics and Gynecology, Lund University Hospital, Sweden. Participants Forty-seven term-pregnant women not in labour who were delivered by caesarean section.Interventions Concentration -response curves with oxytocin and arginine vasopressin on isolated myometrial strips were recorded in control experiments, in the presence of atosiban in concentrations of 25, 250 and 750 nmol/L, and after pretreatment with ANTAG III and FE 200 440, both in concentrations of 2.5, 25 and 250 nmol/L. Main outcome measure pA 2 values (i.e. an index of inhibitory action).Results With oxytocin as the agonist, the median pA 2 values for atosiban, ANTAG III and FE 200 440 were 10.6, 9.5 and 8.3, respectively. With vasopressin as the agonist, the pA 2 values for atosiban and ANTAG III were 8.8 and 8.7, whereas no inhibitory effect of FE 200 440 was seen in five out of six experiments. Conclusion The new analogue FE 200 440 is a selective oxytocin antagonist and, in contrast to atosiban and ANTAG III, has practically no effect on vasopressin-induced contractions of isolated term-pregnant human myometrium.

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Receptor binding of oxytocin and vasopressin antagonists and inhibitory effects on isolated myometrium from preterm and term pregnant women

Cited by 110 publications

References 19 publications

Pharmacologic Chaperones as a Potential Treatment for X-Linked Nephrogenic Diabetes Insipidus

Pharmacologic Chaperones as a Potential Treatment for X-Linked Nephrogenic Diabetes Insipidus

Functions of vasopressin and oxytocin in bone mass regulation

FE 200 440: a selective oxytocin antagonist on the term-pregnant human uterus

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