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)

Prostanoid receptors regulating the contractility of strips of myometrium obtained from nonpregnant ewes during the breeding season were classified pharmacologically. Natural prostanoids, receptor-type selective synthetic analogues, and selective antagonists were used where available. The natural prostanoids PGD2, PGE2, and PGF2 alpha were equipotent in causing contractions (pD2 values of 6.9, 6.7, and 6.9, respectively) but were 100 times less potent than oxytocin (pD2 = 9.2). The synthetic prostanoids iloprost (pD2 = 8.3), GR63799x (pD2 = 7.0), cloprostenol (pD2 = 6.8), and U46619 (pD2 = 6.2) also caused contractions. The effects of iloprost, but not of GR63799x, were blocked by the selective EP1 antagonist AH 6809. This suggests the presence of both EP1 and EP3 receptors. The similar potencies of cloprostenol and PGF2 alpha suggest the presence of FP receptors. Although the potency of the TP agonist U46619 was relatively low, its effects were blocked by the selective TP antagonist L 670596 (pKB = 8.4), an observation consistent with the presence of TP receptors. Thus, all currently recognized excitatory prostanoid receptors (EP1, EP3, FP and TP) appeared to be present. Contractions induced by cloprostenol and KCl could be inhibited by the beta-adrenoceptor agonist isoprenaline (pD2 = 8.8 against cloprostenol) and the Ca(2+)-channel blocker, D600 (pD2 = 6.3 against cloprostenol), but a number of relaxant prostanoids, BW245c, ZK110841, AH13205 and cicaprost, could not produce inhibition. These results suggest that DP, EP2 and IP receptors do not regulate contractility under these conditions.
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PMID:Pharmacological characterization in vitro of prostanoid receptors in the myometrium of nonpregnant ewes. 753 49

PGE2 is a powerful modulator of uterine contractility, but there is uncertainty as to which receptor subtypes (EP1, EP2, EP3, or EP4), G proteins, and second messenger systems are activated by PGE2 in myometrium. Here we show that in cultured human myometrial cells, PGE2 (1-100 microM) activates phospholipase C (PLC) up to 500% over the control level and elevates intracellular calcium ([Ca2+]i) from the resting level of 60-90 nM up to 350 nM in a concentration-dependent manner. Stimulation by the receptor subtype-selective analogs GR63799X (EP3), sulprostone (EP3 > EP1), and misoprostol (EP3 > EP2 > EP1) indicates that these effects are transmitted through EP3 receptors. Both effects are resistant to pertussis toxin (PT). Lower concentrations of PGE2 (1-300 nM) increase [Ca2+]i via a PT-sensitive pathway, without PLC activation. This [Ca2+]i increase occurs after an inverse dose-related delay and is inhibited by the selective EP1 antagonist AH6809 and calcium channel blockers. By comparison, oxytocin stimulates PLC up to 1000% over the control level and elevates [Ca2+]i up to 800 nM in a concentration-dependent manner without any measurable delay; both effects are partly sensitive to PT. These data provide functional evidence for the presence of different stimulatory mechanisms for PGE2 in myometrium: 1) a low affinity receptor (probably EP3D) that activates PLC through a PT-insensitive pathway; and 2) a high affinity receptor (probably EP1), independent from PLC and involving a PT-sensitive G protein (G(i)?). Both pathways lead to elevation of [Ca2+]i.
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PMID:Prostaglandin E2 activates phospholipase C and elevates intracellular calcium in cultured myometrial cells: involvement of EP1 and EP3 receptor subtypes. 864 Dec 11

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

Prostaglandins (PGs) have been implicated in the regulation of vasopressin (VP) and oxytocin (OT) release in response to various stimuli. To examine the site and mechanism of actions of PGs, we studied effects of PGE2 and PG-receptor agonists on supraoptic nucleus (SON) neurones of rat hypothalamic slice preparations using extracellular recording and whole-cell patch-clamp techniques. PGE2 modulated the electrical activity of more than 80% of the neurones studied. The effects of PGE2 on both phasic and non-phasic neurones were mostly excitatory, and dose-dependent. The effects of PGE2 were mimicked by PGF2alpha or the FP agonist, fluprostenol, whereas PGD2 or the selective EP, IP or TP agonist was less effective or had no effect. The effects of PGE2 were unaffected by the EP1 antagonist, SC-51322, but reduced to 80% of control by the EP1/FP/TP antagonist, ONO-NT-012, which reduced the effects of fluprostenol to 32% of control. Moreover, some neurones responsive to PGE2 did not respond to fluprostenol. Patch-clamp analysis in SON slice preparations revealed that PGE2 at 10(-6) M depolarized the membrane potential by 3.9+/-0.3 mV from the resting membrane potential of -58.4+/-2.2 mV in the current-clamp mode. In the voltage-clamp mode, PGE2 induced inward currents at a holding potential of -70 or -80 mV, while it did not affect spontaneous excitatory postsynaptic currents. PGE2 induced currents also in dissociated SON neurones and the reversal potential of the currents was -35.5+/-0.9 mV, which was similar to that of currents induced by fluprostenol. These results suggest that SON neurones possess at least two types of PG receptors, FP receptors and EP receptors of a subclass different from EP1, EP2, or EP3, and that activation of these receptors leads to the opening of nonselective cation channels, membrane depolarization and increase of the action potential discharge.
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PMID:Actions of prostaglandin E2 on rat supraoptic neurones. 987 Jul 50

The increased expression of contraction-associated proteins, including oxytocin receptors, connexin-43, and prostaglandin F2alpha receptors, in term pregnant myometrium is classically considered to be the concrete expression of myometrial activation. However, the decrease in prostaglandin E2 receptor subtype EP2 on one hand and the down-regulation of the nitric oxide (NO) pathway and various vasorelaxing peptides on the other hand probably also play a key role in the loss of quiescence, and, with the above-mentioned activation, in the maturation of the myometrium. Decidual activation and production of interleukin-1, tumour necrosis factor-alpha and epidermal growth factor enhance prostaglandin production in both the amnion and chorion, and also in the myometrium. A substantial increase of eicosanoids concentration in myometrial tissue is probably an important condition for the success of the ultimate step of myometrial stimulation and the onset of labour. During labour, prostaglandins and oxytocin seem to act in synergy, perhaps along with endothelin-1, to trigger contractility through an increase in intracellular Ca2+ concentration. An overall view of these phenomena in which myometrial cells are the common targets of uterorelaxant and uterotonic agents appears essential for a rational use of tocolytic therapies and labour inductors.
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PMID:Myometrial maturation and labour. 1181 51

The aim of this study was to compare the effect of two known spasmogens, oxytocin and the stable thromboxane receptor mimetic, U46619, on human myometrium treated with the prostaglandin E receptor (EP2) agonist, butaprost (selective for the EP2 receptor). Strips of myometrium from pregnant and non-pregnant donors were set up in a superfusion apparatus. Butaprost was administered as a bolus dose and via infusion. During the infusion of 10(-6) M butaprost, spasmogens were administered as bolus doses. Butaprost caused dose-related inhibition of myometrial activity when administered as a bolus dose (3-100 nmol) and concentration-dependent inhibition during infusion studies (10(-8)-10(-5 )M). Butaprost (10(-6 )M) attenuated the response to U46619 (0.l-10 nmol) in pregnant myometrium, but this difference was not statistically significant. Responses of pregnant myometrium to oxytocin (0.01-0.1 nmol) were significantly attenuated (P<0.05) in the presence of butaprost (10(-6)M). Butaprost physiologically antagonised the oxytocin response, possibly by increasing intracellular cAMP levels. This antagonism was much more marked than that seen with butaprost and U46619. It is unclear why these two types of antagonism differ and this effect is currently being investigated further using other prostanoid and non-prostanoid agents.
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PMID:An investigation of the effect of the prostaglandin EP2 receptor agonist, butaprost, on the human isolated myometrium from pregnant and non-pregnant women. 1183 44

The mechanism of labour is not fully understood and further research into this important physiological process is needed. In some species, notably sheep, parturition is due to activation of the fetal hypothalamic-pituitary-adrenal axis. However, in primates, this axis appears to have a supportive, rather than essential role. Successful parturition requires an increase in coordinated uterine contractility together with changes in connective tissue that allow cervical ripening and dilatation. In most mammals, however, these changes are synchronised by a fall in maternal progesterone levels and a rise in oestrogens. This is not the case in women in whom the onset of labour occurs without apparent changes in circulating steroid levels. The basis of uterine contractility is the interaction between actin and myosin in myometrial smooth muscle cells. This is driven by calcium through Ca(2+)-calmodulin-dependent myosin light chain kinase (MLCK) activity. Moreover, calcium sensitisation occurs via activation of Rho kinase, a calcium-independent pathway that promotes contractility by inhibiting myosin phosphatase and probably by phosphorylating myosin on the same site as MLCK. Uterine activity can be modulated by many G-protein coupled receptors (GPCRs). For example, receptors coupled to Galpha(q) (oxytocin-, prostanoid FP and TP, endothelin-receptors) stimulate contractility by activating the phospholipase C/Ca(2+) pathway; receptors coupled to Galpha(s) (beta(2)-adrenoceptors, prostanoid EP2 and IP, some 5-hydroxytryptamine receptors e.g. 5-HT(7)) relax the uterus by increasing myometrial cyclic AMP levels; and receptors coupled to Galpha(i) (alpha(2)-adrenoceptors, muscarinic, 5-HT(1)) potentiate contractility, probably by inhibiting cAMP production. Because of its relative abundance in pregnant uterine tissue, the oxytocin receptor is an obvious target for tocolytic therapy. Oxytocin antagonists have been introduced into clinical practice for the management of preterm labour and offer the advantage of uterine selectivity and fewer side effects than conventional beta-agonist therapy.
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PMID:Mechanisms of labour--biochemical aspects. 1276 10

The neurohypophyseal hormone oxytocin (OT) plays critical roles in lactation and parturition, while its function in male reproduction system is largely unknown. This study aims to investigate the effect of OT on regulating transepithelial ion transport in rat cauda epididymal epithelium. With the use of RT-PCR, Western blot, and immunohistochemical analysis, we found that OT receptor (OTR) was expressed and localized at the basal membrane of rat cauda epididymal epithelium. The short-circuit current (Isc) measurement showed that basolateral application of OT to the primary cultured rat cauda epididymal epithelial cells elicited an increase in Isc, which was abrogated by pretreating the epithelial cells with CFTRinh-172, a blocker of cystic fibrosis transmembrane conductance regulator (CFTR). Pretreatment with the prostaglandin H synthase inhibitors indomethacin and piroxicam, or the nonselective antagonists of prostaglandin E2 (PGE2) receptor EP2 or EP4, AH-6809, and AH-23848, significantly attenuated OT-stimulated Isc response. Furthermore, the generation of PGE2 was measured using enzyme-linked immunosorbent assay, demonstrating that OT induced a substantial increase in PGE2 release from primary cultured rat cauda epididymal epithelial cells. In conclusion, activation of OTR by OT triggered PGE2 release, resulting in CFTR-dependent Cl- secretion through paracrine/autocrine pathways in rat cauda epididymal epithelium.
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PMID:Cellular mechanism underlying oxytocin-stimulated Cl- secretion in rat cauda epididymal epithelium. 3272 60