Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01178 (oxytocin)
 15,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Direct measurements of cyclic AMP were performed in the isolated epithelium of frog skin. Phosphodiesterase inhibitors (methylxanthines, papaverine) and activators of adenylyl cyclase (oxytocin, catecholamines) significantly increased the cyclic AMP content. Propranolol completely blocked the generation of cAMP induced by beta-adrenergic agonists but had little or no effect on that induced by oxytocin. Phentolamine enhanced the cAMP production by adrenalin and noradrenalin. At supramaximal concentrations, oxytocin and isoproterenol produced similar increments in cAMP, while exposure to both agents roughly doubled the increase in cAMP. The results suggest the presence of independent receptors for oxytocin and catecholamines in frog skin, with additive effects on cAMP generation.
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PMID:Cyclic AMP levels in isolated frog skin epithelium: effects of phosphodiesterase inhibitors, oxytocin and catecholamines. 21 57

Increased expression of the oxytocin gene of ruminants is associated with the process of luteinization both in vivo and in vitro. Cell culture studies and measurements of mRNA in luteal extracts have confirmed that the gene is switched on in the preovulatory follicle about 24 h before ovulation, at the time of the gonadotrophin surge. It is downregulated again equally rapidly after ovulation, so that by day 2 of the cycle the capacity of the luteal cells to make oxytocin has already been greatly reduced. A number of factors can increase oxytocin production by luteinizing granulosa cells. They include oestradiol and compounds such as gonadotrophins and catecholamines which are known to act by increasing intracellular concentrations of adenylyl cyclase. However, all of these factors are ineffective if the follicle is collected too early, suggesting that an initial maturation step is necessary to develop responsiveness. Analysis of the promoter region of the bovine oxytocin gene has indicated that neither oestradiol nor cAMP can directly initiate activation; instead regulation appears to occur via a COUP factor binding site. Additional transacting nuclear proteins may therefore be required to act as intermediaries. The same factors that initially stimulate oxytocin production switch to inhibiting production shortly after ovulation, leading to downregulation of the gene. After translation of oxytocin mRNA during the luteal phase, oxytocin precursor is packaged into secretory granules in the large luteal cells. Processing involves a series of enzymatic steps, culminating in amidation to produce oxytocin. Cultured cells may secrete intermediate forms of partially processed peptide, but it is not known if this also occurs in vivo. Oxytocin release from the cell involves granule exocytosis which is probably triggered by an increase in intracellular calcium. During luteolysis this is regulated by the release of prostaglandin F2 alpha (PGF2 alpha) from the uterus, although additional factors may also contribute. Neither PGF2 alpha nor catecholamines appear to be prime regulators of luteal oxytocin release during the early and mid-luteal phases of the cycle and it remains to be determined how secretion is controlled at this time.
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PMID:Control of synthesis and secretion of ovarian oxytocin in ruminants. 130 33

In this study we compare the uterine contractility and beta-adrenergic receptor effects of identical doses of ritodrine administered intermittently or continuously for 24 hours in pregnant sheep. Ritodrine was administered intravenously to five animals as a pulse, 16 micrograms/kg every 1.5 hours, whereas five other animals received ritodrine as a continuous infusion of 0.18 microgram/kg/min. Ritodrine plasma concentrations at steady state were comparable in both groups and averaged 18 ng/ml. Animals receiving ritodrine pulses demonstrated no alteration of myometrial beta-adrenergic receptors or adenylyl cyclase activity, and ritodrine inhibited oxytocin-induced contractility comparably at 4 and 24 hours. Animals receiving ritodrine continuously had a significant decrease in myometrial beta-adrenergic receptors and adenylyl cyclase activity, yet ritodrine inhibition of oxytocin-induced uterine contractility was sustained for 24 hours. Oxytocin receptors were not affected by ritodrine administration and were similar in both groups. At the dose studied, oxytocin-induced contractions are comparably inhibited by ritodrine for 24 hours whether the drug is given continuously or in a pulsatile fashion.
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PMID:Comparison of pulsatile and continuous ritodrine administration: effects on uterine contractility and beta-adrenergic receptor cascade. 184 3

Immediate-early genes, such as c-fos, couple extracellular signals to genetic changes in the cell. We have previously demonstrated that depolarization with 50 mM KCl increases Fos immunoreactivity in hypothalamic tyrosine hydroxylase (TH) and oxytocin immunoreactive (-ir) neurons in primary culture. This Fos activation occurs within 1.5-2 h in TH-ir cells. In the present study, we examined the effects of depolarization, glutamate receptor activation and adenylyl cyclase stimulation on Fos-ir to determine the possible mechanism(s) of Fos activation in TH-ir neurons. Hypothalamic cultures were treated with KCl, glutamate or forskolin, and Fos and TH were visualized immunocytochemically. Forskolin increased the percentage of Fos/TH-ir neurons in a dose-dependent manner, with a maximal stimulation of 53.4 +/- 4.5% Fos/TH-ir neurons at 30 microM forskolin. The dose-response curve for glutamate was steep, with a maximal stimulation of 24.8 +/- 2.1% Fos-ir neurons at 100 microM. 50 mM KCl resulted in 50.0 +/- 0.8% Fos/TH-ir neurons. Pretreatment with verapamil decreased KCl induced Fos-ir by 57%, glutamate by 65% and forskolin by 39%. Combined drug administration demonstrated significant additivity between forskolin and glutamate, and forskolin and KCl, however, no significant additivity was found with KCl and glutamate. The results are discussed in terms of cAMP and calcium mediation of the Fos response to these stimuli.
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PMID:Calcium and cAMP mediated stimulation of Fos in cultured hypothalamic tyrosine hydroxylase-immunoreactive neurons. 798 47

Forskolin (FSK; an activator of adenylyl cyclase) and cortisol synergistically increase the concentration of oxytocin receptors (OTRs) in rabbit amnion cells. The aims of this study were to characterize potential physiological regulators of OTR concentrations acting through adenylyl cyclase and to clarify the mechanisms of potentiation by cAMP and cortisol. Both isoproterenol (ISO) and parathyroid hormone-related protein (PTHrP) elevated amnion cell cAMP levels and OTR concentrations. The effects of ISO and PTHrP on OTR were potentiated by cortisol. Cortisol had no effect on the ability of ISO or PTHrP to stimulate adenylyl cyclase activity, and cAMP did not affect the number or affinity of glucocorticoid receptors in whole cells or in cytosol. Adenylyl cyclase activation, however, caused conversion of mifepristone (RU486) from a glucocorticoid antagonist to agonist. Thus, mifepristone elevated OTR receptor concentrations in the presence of FSK. In contrast, a structurally related glucocorticoid antagonist, onapristone (ZK98 299), was unaffected by cAMP. Because glucocorticoid receptors bound to mifepristone are capable of interacting with DNA, whereas onapristone-occupied receptors are not, we conclude that cAMP affects glucocoticoid receptor-DNA interactions, accounting for the synergistic effects of cAMP and cortisol on OTRs.
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PMID:Effectors of cyclic adenosine 5'-monophosphate up-regulating-oxytocin receptors in rabbit amnion cells: isoproterenol, parathyroid hormone-related protein, and potentiation by cortisol. 852 7

Melanophore pigment dispersion is a sensitive bioassay for activation of the adenylyl cyclase and phospholipase C second-messenger pathways. The necessity of protein kinase activation in causing pigment dispersion was confirmed for eight agonists of endogenous melanophore receptors and for two transfected receptors. All agonists and receptors previously shown to elevate intracellular cAMP in melanophores--melanocyte stimulating hormone, light, (-) norepinephrine, 5-hydroxytrptamine, and the beta2-adrenergic receptor--were able to stimulate pigment dispersion in the presence of Ro31-8220, a potent inhibitor of protein kinase C, but were blocked in the presence of H89, an inhibitor of cAMP-dependent protein kinase. The bombesin receptor, which elevates intracellular IP3 in melanophores, was unable to stimulate pigment dispersion in the presence of Ro31-8220 or H89. Agonists whose mechanism of activation of pigment dispersion are unknown were also tested. Endothelin 3 responses were blocked by both H89 and Ro31-8220, predicting coupling to phospholipase C. Vasoactive intestinal polypeptide, oxytocin, and calcitonin gene-related peptide beta responses were blocked only by H89, predicting coupling to adenylyl cyclase.
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PMID:Melanophore pigment dispersion responses to agonists show two patterns of sensitivity to inhibitors of cAMP-dependent protein kinase and protein kinase C. 869 26

Pulsatile secretion of endometrial prostaglandin (PG)F2 alpha is stimulated by oxytocin (OT) during late diestrus in domestic ruminants (i.e., cattle, sheep and goats) and results in corpus luteum (CL) regression leading to the onset of a new estrous cycle. Pulsatile PGF2 alpha release is also responsible for CL regression in swine, but the stimulus for its secretion from the uterine endometrium is not known. We propose that OT binds to specific OT receptors (OTR) on the endometrium to stimulate phosphoinositide (PI) hydrolysis, thereby activating the inositol trisphosphate (IP3)-diacylglycerol (DAG) second-messenger system to promote pulsatile PGF2 alpha secretion. Exogenous OT administered to cyclic gilts during late diestrus (days 10-16) decreased interestrous interval in three of four experiments. However, OT did not promote CL regression in hysterectomized gilts indicating that the effect of OT was uterine-dependent. Circulating concentrations of 13,14-dihydro-15-keto PGF2 alpha (the major stable metabolite of PGF2 alpha) were increased (p < 0.01) 10 min after i.v. injection of OT on days 14 and 16 in cyclic gilts and on days 10-16 in pregnant gilts, but the magnitude of the response to OT on all days in pregnant gilts was markedly reduced compared to the response in cyclic gilts on days 14 and 16. Mean density and Kd of OTR detected on endometrium of cyclic pigs 15 days post-estrus were 29.2 +/- 5.5 fmol/mg protein and 1.59 +/- 0.23 nM, respectively. Density of OTR was correlated with OT-stimulated PI hydrolysis (r = 0.83, p < 0.05) and PGF2 alpha secretion (r = 0.87, p < 0.10). Endometrial IP3 was increased within 30 seconds after OT treatment and preceded the increase in PGF2 alpha release stimulated by OT. Endometrial PI hydrolysis and PGF2 alpha secretion were similarly increased by AIF4-(phospholipase C activator), but not by cholera toxin (adenylyl cyclase activator). Although OT binding to OTR could be displaced by lysine-vasopressin and lysine-vasopressin stimulated PI hydrolysis, lysine-vasopressin did not stimulate PGF2 alpha release. Distinct receptors for OT and lysine-vasopressin on pig endometrium were confirmed by treatment with 100 nM OT + 100 nM lysine-vasopressin which stimulated PI hydrolysis more than 100-200 nM OT or lysine-vasopressin alone. These results support the hypothesis that OT stimulates phospholipase C to hydrolyze PI, yielding IP3 and DAG second-messengers which promote endometrial PGF2 alpha release during CL regression in pigs.
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PMID:A proposed role for oxytocin in regulation of endometrial prostaglandin F2 alpha secretion during luteolysis in swine. 871 96

Parturition results from the establishment of phasic regular uterine contractions. Contractility in myometrial smooth muscle is stimulated by an increase in intracellular calcium ([Ca2+i]) which activates myosin light chain phosphorylation leading to increased myosin ATPase activity and enhanced rate of acto-myosin cross bridge formation. G proteins play a pivotal role in smooth muscle activation and relaxation by coupling cell membrane receptors to effector enzymes and ion channels. G alpha(s) and G alpha(i) stimulate and inhibit adenylyl cyclase, respectively and control cAMP formation. G alpha(q) stimulates phospholipase C resulting in the formation of two second messengers: inositol 1,4,5-trisphosphate (InsP3) which releases Ca2+ from the sarcoplasmic reticulum, and 1,2-diacylglycerol which activates protein kinase C. The oxytocin receptor stimulates myometrial contractility by increasing [Ca2+i] through both pertussis toxin resistant (G alpha(q)) and pertussis toxin sensitive (?G alpha (i)) pathways. beta-Adrenoceptors and prostaglandin EP2 receptors promote relaxation via G alpha(s)-adenylyl cyclase. The concentration of myometrial oxytocin receptors is five-times higher in pregnant compared to non-pregnant myometrium but decreases in samples obtained during labour. When myometrial slices are challenged with oxytocin there is a rapid increase in InsP3 levels with a time course which is similar to the rise in [Ca2+i] provoked by oxytocin in cultured myometrial cells. The formation of InsP3 in response to oxytocin in myometrial tissue at term is similar in samples obtained before and after the onset of labour. G alpha(q) and G alpha(i) are expressed at similar levels in non-pregnant and in pregnant myometrium obtained before or during labour. By contract, G alpha(s) levels are higher in pregnant compared to non-pregnant myometrium and decrease in samples obtained during labor. These changes in G alpha(s) are paralleled by prostaglandin E2-induced adenylyl cyclase activity in the same tissues. Parturition may be the consequence of downregulation of pathways that favour uterine quiescence by increasing cAMP formation, resulting in a relative dominance of stimulatory receptors that increase InsP3/Ca2+ availability.
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PMID:Parturition: activation of stimulatory pathways or loss of uterine quiescence? 871 97

The purpose of this study was to determine in vivo the dose response relationship between beta-adrenergic receptor (BAR) agonist concentration and various elements of the BAR cascade: receptor density, hormone-stimulable adenylyl cyclase activity, and contraction inhibition. A previously described, chronically-catheterized ovine model was used. Ritodrine was infused continuously over 24 h in 22 mixed-breed sheep. Each animal received a single, constant infusion rate. Myometrial biopsies were obtained before and after the drug infusions. BAR density was determined using tritiated dihydroalprenolol. Adenylyl cyclase activity was determined using the Gilman competitive protein-binding assay. Intermittent oxytocin boluses were given into the maternal aorta and contractile response was determined. Infusion rates of 0.06-4.0 micrograms/kg/min yielded steady-state ritodrine serum concentrations of 5-168 ng/ml. No significant correlation was found between the ritodrine concentration and the magnitude of decrease in BAR density. Significant correlations existed, however, between the ritodrine concentration and both the magnitude of decrease in adenylyl cyclase activity and the loss of contraction inhibition. There was no correlation noted between the BAR cascade alterations and the loss of contraction inhibition. Despite significant reductions in receptor density (down regulation) and dose-related reductions in hormone-stimulable adenylyl cyclase activity (uncoupling), ritodrine at low concentrations was still able to inhibit oxytocin-induced contractions, i.e., tachyphylaxis did not occur. Tachyphylaxis appeared to correlate only with the serum ritodrine concentration. Hence, alterations in the BAR cascade do not necessarily equate with a loss of end-organ response (tachyphylaxis). Previous concepts based on in vitro studies about the interaction of the BAR agonist with its receptor, the subsequent generation of intracellular messengers, and the resultant end-organ response may not apply in the intact animal.
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PMID:Alterations in ovine myometrial beta-adrenergic cascade do not mediate tachyphylaxis to ritodrine. 879 87

The effects of arginine vasotocin (AVT) were examined in isolated gar arteries (afferent branchial, ABA; conus arteriosus, CA; ventral aorta, VA) and veins (hepatic, HV; intestinal; ovarian). AVT (10(-11) - 10(-7) M) had no effect in CA, produced contraction in ABA and VA and stimulated relaxation in veins. In precontracted HV, AVT relaxation was dose-dependent, long-lived (> 30 min) and reduced total tension by 49.0 +/- 10.7%. EC50s for AVT, arginine vasopressin, oxytocin, desmopressin, and isotocin in gar HV were 1.4 +/- 0.3, 3.6 +/- 0.2, 5.3 +/- 1.7, 11.0 +/- 6.5, and 19.0 +/- 0.4 nM, respectively. AVT was more potent compared with isotocin. Strength of relaxation (percentage decrease in total tension) of AVT and structural analogs was similar (range = 32.5 to 55%). Endothelium removal did not alter percentage relaxation or sensitivity to AVT in HV. AVT relaxation was not inhibited by nitric oxide synthase inhibitors or propranolol or reversed by addition of methylene blue but it was significantly enhanced by indomethacin (10(-5) M). Arginine vasopressin-receptor antagonists (V1- or V2-type selectivity; 10(-6) M) were equally effective inhibitors, each blocked 99% of AVT relaxation. Forskolin (10(-6) M) and papaverine (10(-4) M) relaxed precontracted gar arteries and veins. The adenylyl cyclase inhibitors SQ 22536 and MDL 12,330A (10(-5) M) produced transient contraction and stable relaxation, respectively, but did not inhibit AVT-induced relaxation in HV. Atrial natriuretic peptide (3 x 10(-8) M) and sodium nitroprusside (10(-4) M) had no effect in precontracted HV. AVT acts directly on gar venous smooth muscle cells via a nonclassical AVP receptor, possibly by increasing [cAMP]. AVT is a potent vasoconstrictor in vertebrate vasculature but produces a novel relaxation in gar veins.
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PMID:Arginine vasotocin relaxation of gar (Lepisosteous spp.) hepatic vein in vitro. 892 55


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