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Query: UNIPROT:P01185 (vasopressin)
 23,126 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite intensive efforts over three decades in many laboratories, attempts to design peptide antagonists of oxytocin (OT) which are more selective for OT uterine receptors than for vasopressin (AVP), vasopressor V1a receptors, have met with only limited success. We will review the current status of the field and report on studies in our laboratories which have led to the design of highly potent non-selective and selective OT antagonists. Virtually all are more potent (2-6 fold) and a number are more selective (10-12 fold) than Atosiban, currently in clinical trial as a tocolytic agent. Many of these new published and unpublished OT antagonists are thus promising candidates for development as potential tocolytic agents for the prevention of pre-term labor. We also report on promising new radioiodinatable ligands for OT receptors. All the new OT antagonists are valuable new tools for studies on the physiological roles of OT and as probes for OT and AVP receptors.
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PMID:Advances in the design of selective antagonists, potential tocolytics, and radioiodinated ligands for oxytocin receptors. 871 21

1. The exact nature of the receptor subtype(s) involved in the action of arg-vasopressin (AVP) on the rat aorta and small mesenteric artery (SMA) is controversial. Therefore, we have studied the effects of the selective V1A receptor antagonists, OPC 21268 and SR 49059, and the oxytocin (OT) receptor antagonist, atosiban, on the AVP- and OT-induced contractions of the two vessels. 2. AVP and OT displayed similar intrinsic activities in the rat aorta and SMA, but AVP was approximately 130 fold and approximately 500 fold more potent than OT, respectively. In the rat aorta, Hill slopes (nH) were similar for OT and AVP. However, in rat SMA, the OT concentration-effect (E/[A]) curve was significantly steeper than the AVP E/[A] curve (nH, = 3.3+/-0.20, 2.3+/-0.15; P<0.001). 3. In the aorta OPC 21268, SR 49059 and atosiban competitively antagonized the AVP and OT E/[A] curves. Except for atosiban and SR 49059 against AVP, competitive antagonism was also observed in the SMA. Atosiban caused concentration-dependent steepening of the AVP E/[A] curve, whereas SR 49059 decreased the upper asymptote. 4. Schild analysis yielded affinities indicative of V1A receptor involvement in both vessels: pKB/ pA2=9.20 9.48, 7.56 7.71 and 6.19 6.48 for SR 49059, OPC 21268 and atosiban, respectively. 5. Neither AVP nor OT relaxed U46619 pre-contracted aorta or SMA in the presence of SR 49059, suggesting no interference of a vasodilatory component. 6. Despite predominant involvement of V1A receptors in both vessels, the different Hill slopes of AVP and OT E/[A] curves as well as the steepening of the AVP E/[A] curves by atosiban are indicative of receptor heterogeneity in the rat SMA.
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PMID:Characterization of receptors mediating contraction of the rat isolated small mesenteric artery and aorta to arginine vasopressin and oxytocin. 983 26

Oxytocin is involved in the regulation of preterm and term labor but the exact effect mechanisms are not fully understood. A regulatory action by vasopressin may also exist. The concentrations of oxytocin and vasopressin V1a receptors in myometrium from pregnant women are high before and in the beginning of labor both preterm and at term. Atosiban has high affinity for both these receptors and is a competitive oxytocin and vasopressin antagonist. The inhibitory effect of Atosiban on oxytocin induced activity on isolated myometrium correlates significantly with the concentration of the oxytocin receptors. Inhibition of preterm contractions with Atosiban was first reported by Akerlund et al 1987. Goodwin et al compared the effect of Atosiban to placebo in threatening preterm labor and the antagonist was in this trial significantly more effective than placebo in reducing the frequency of contractions (55% vs. 23%, p < 0.001). The same authors also reported successful tocolysis with the drug in actual preterm labor. Atosiban is currently in phase III of clinical development and seems to have the same effectiveness but fewer side-effects compared to beta-mimetics. These properties suggests that Atosiban may offer advantages over existing therapies in acute treatment of preterm labor.
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PMID:Treatment of preterm labor with the oxytocin and vasopressin antagonist Atosiban. 1022 2

We compared menstrual pain, uterine contractility and blood circulation, and plasma concentrations of vasopressin and prostaglandin F(2alpha) metabolite in women with versus without primary dysmenorrhea, and determined the effects of a vasopressin antagonist, 1-deamino-2-D-Tyr(OEt)-4-Thr-8-Orn-oxytocin (Atosiban), on these parameters. Our results do not support the contention that vasopressin is involved in the etiology of dysmenorrhea, plasma concentrations of vasopressin being similar in dysmenorrheic women and controls, and the vasopressin antagonist Atosiban having no effect on menstrual pain, intrauterine pressure or uterine artery pulsatility index in dysmenorrheic women.
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PMID:Effects of a vasopressin antagonist in women with dysmenorrhea. 1101 49

Preterm delivery is the largest cause of perinatal mortality and morbidity, yet the treatment of preterm labour has not been demonstrated to improve outcome. The reasons are numerous and complex, but they include a failure to understand the mechanism(s) of preterm labour, the multitude of different causes, the difficulty in diagnosis and the problems of outcome measurement in clinical trials. Recently, an oxytocin antagonist (atosiban) has been introduced into clinical practice in Europe. Although it may be an effective tocolytic, a beneficial effect on perinatal outcome has not been demonstrated. Atosiban has an effect at both oxytocin and vasopressin (V(1a)) receptors, which (assuming efficacy) raises the question as to whether oxytocin or vasopressin V(1a) antagonism is required for tocolysis. This review examines the rationale for tocolysis in preterm labour, the evidence for administration of atosiban and the role for oxytocin, vasopressin and their receptors in the onset of labour. Experimental Physiology (2001) 86.2, 297-302.
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PMID:Oxytocin antagonists: clinical and scientific considerations. 1169 80

Important sources of oxytocin and vasopressin in the human, apart from the supraoptic and paraventricular nuclei of the brain, may be the fetus during labor as well as the endometrium and decidua of the uterus itself. The release of oxytocin and vasopressin to plasma is under influence of ovarian steroids. The two hormones stimulate uterine contractions in pregnant and non-pregnant women via myometrial oxytocin and vasopressin V1a receptors. At the onset of human labor preterm or at term no clear rise in the maternal plasma concentration of oxytocin and/or vasopressin has been demonstrated, but there may be an increased pulse frequency of the release of oxytocin to plasma with the advance of labor. Vasopressin is more potent than oxytocin on isolated myometrium from women undergoing Cesarean section at term. The myometrial concentration of the two receptors is about equal. At the onset of labor preterm and at term there is a tendency to an increase in the density of oxytocin and vasopressin V1a receptors, but there may be a heterogeneous expression of at least the former receptor between different myometrial cells. In advanced labor or after oxytocin treatment the receptors are markedly downregulated. The importance of oxytocin and vasopressin in mechanisms of preterm labor is confirmed by the therapeutic effect in the condition of the oxytocin and vasopressin V1a receptor blocking oxytocin analogue, atosiban. In women with primary dysmenorrhea the plasma concentration of vasopressin is elevated. The in vivo effect of vasopressin on uterine activity in non-pregnant women is about five times more pronounced than that of oxytocin, and it increases premenstrually. Correspondingly, the density of vasopressin V1a and oxytocin receptors vary to the same degree, and a premenstrual rise in the former receptor is seen. Atosiban and the non-peptide compound, SR 49059, which binds to the two receptors in a similar way as atosiban, are therapeutically effective in dysmenorrhea.
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PMID:Involvement of oxytocin and vasopressin in the pathophysiology of preterm labor and primary dysmenorrhea. 1243 49

The perfect tocolytic agent, which is completely safe for both the mother and fetus and, which will inhibit uterine contractions and stop preterm labour in every case does not exist and the search continues. Recently, research into a new group of tocolytic agents (the oxytocic antagonists) has led to the introduction of a new licensed drug, atosiban. Since the early 1950s, modifications of the oxytocin molecule have resulted in many analogues and antagonists, though initially none emerged as potentially useful drugs. Further modifications resulted in full uterotonic antagonism in animal models before an analogue was found that inhibited vasopressin-stimulated uterine contractions in non-pregnant healthy women. In vitro and animal models suggested the molecule was fully antagonistic, although it was found to be only partially agonistic in women. Further developments led to two modified oxytocin molecules with higher receptor affinity for human myometrium, both of which lacked agonism in humans. The analogue, atosiban, was found to be more potent and so was chosen for clinical evaluation in dysmenorrhoea and preterm labour. The first clinical reports were open label, observational pilot studies. Randomised, double-blind, phase II placebo-controlled studies followed showing that atosiban was significantly more effective than placebo with very few side effects. Dose-response studies and phase III studies in which study or placebo groups could use alternative tocolytic agents also suggested that atosiban was an effective tocolytic agent with very few adverse events. The recent worldwide comparative study of atosiban versus different beta-agonists represents the largest and most strictly controlled study of tocolytics ever published. Atosiban was found to be at least as effective as the beta-agonists as a tocolytic agent, but significantly less likely to result in maternal cardiovascular side effects or the need to discontinue therapy as a result of unacceptable side effects.
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PMID:The development and introduction of anti-oxytocic tocolytics. 1276 25

In adult animals, peptide hormones, including oxytocin and arginine vasopressin, have been implicated in both parental behavior and the modulation of anxiety. The purpose of this study was to examine the consequences of developmental manipulations of oxytocin for the later expression of alloparental behavior as well as behavioral responses to a novel environment, the elevated plus maze (EPM). Prairie voles (Microtus ochrogaster), a cooperatively breeding species, were selected for this study. On neonatal Day 1, pups received an ip injection of oxytocin or oxytocin antagonist, or were controls, receiving either saline or handling only. At 21 and approximately 60 days of age, each animal was tested for parental care toward novel stimulus pups. At approximately 67 days, an EPM test was administered. Control females at 60 days of age were more likely to attack pups and spent less time in the open arm of the EPM, both of which might reflect higher levels of anxiety in females than males. In males, neonatal treatment with oxytocin antagonist was associated with reductions in parental care, especially during the initial exposure to pups on Day 21. Female behavior was not significantly changed as a function of neonatal treatments. Findings to date implicate vasopressin in the behavioral changes in males, that in later life followed a single exposure to an oxytocin antagonist, and suggest caution in the clinical use of agents such as Atosiban, which may have the potential to influence infant development.
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PMID:Sex differences and developmental effects of manipulations of oxytocin on alloparenting and anxiety in prairie voles. 1499 63

We recently found that the oxytocin receptor (OTR) is expressed in the human and rabbit corpus cavernosum and mediates contractility in vitro. The present study extended our investigations to the rat, and explored whether OTR regulates penile detumescence in vivo. Real-time RT-PCR quantitatively characterized the distribution of OTR mRNA in the male genital tract. Specific transcripts for OTR were expressed in all the tissues investigated. Penile expression of OTR was comparable to that observed in testis and prostate. Western blot analysis detected a single band of the expected molecular mass for OTR in all tissues examined, including rat penis. Expression of OTR protein in rat penile extracts was further confirmed by binding studies, using the OTR selective radiolabeled ligand 125I-OTA (K(d) = 17 +/- 6.5 pM, B(max)=15.7 +/- 5 fmoles/mg protein). OTR was immunolocalized to the endothelial and smooth muscle compartments of cavernous spaces and blood vessels. In rat corpus cavernosum strips, oxytocin (OT) and an OTR selective agonist ([Thr4,Gly7]OT) induced identical increases in tension, while different vasopressin agonists were less active. In vivo, OT intra-cavernous injection (ICI) dose-dependently inhibited intracavernous pressure (ICP) increase elicited by either electrical stimulation of the cavernous nerve or ICI of papaverine with similar IC(50)s (117.7 +/- 37 mU). The OTR antagonist, atosiban, counteracted the contractile effect of OT both in vitro and in vivo. Atosiban alone significantly increased ICP at lower stimulation frequencies (2 Hz = P<0.001 and 4 Hz = P<0.05 vs control), but not at the maximal frequency (16 Hz). Our data showed that OTR is present in the rat penis and mediates contractility both in vitro and in vivo, therefore suggesting a role for OT in maintaining penile detumescence.
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PMID:Identification, localization and functional in vitro and in vivo activity of oxytocin receptor in the rat penis. 1574 15

Preterm birth is the major cause of neonatal mortality and morbidity in the developed world. The perfect tocolytic that is uniformly effective with complete fetomaternal safety does not exist. Tocolytic agents differ in cost, utero-specificity, safety, efficacy and whether they are licensed for use. The main three agents that are used worldwide are beta-agonists, Ca(2+) channel blockers and vasopressin/oxytocin receptor antagonists. beta-Agonists are gradually being phased out of use and are being replaced by either nifedipine or atosiban. The evidence base for atosiban is strong but the evidence is of poor quality for nifedipine. The balance of evidence indicates that atosiban is as effective as nifedipine and more effective than beta-agonists and is significantly safer than both. Atosiban was developed specifically to treat preterm labor, so the cost is higher than nifedipine or ritodrine. However, the cost of a course of atosiban (approximately 200 pounds) should not only be considered in comparison with other tocolytic agents but to other medical budgets (e.g., oncology, fertility, cardiology and psychiatry) and to the huge healthcare costs associated with the morbidity and mortality caused by preterm birth. Atosiban is a new advance in the management of spontaneous preterm labor.
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PMID:The choice of a tocolytic for the treatment of preterm labor: a critical evaluation of nifedipine versus atosiban. 1750 96


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