dinoprost and butaprost

Oviductal glycoprotein 1 (OVGP1), an oviductin, is involved in the maintenance of sperm viability and motility and contributes to sperm capacitation in the oviduct. In this study, the regulatory effects exerted by prostaglandin E

Topics: Abattoirs; Alprostadil; Animals; Calcium Signaling; Cattle; Cells, Cultured; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Dinoprost; Dinoprostone; Female; Gene Expression Regulation; Glycoproteins; Oviducts; Prostaglandins F, Synthetic; Protein Isoforms; Protein Kinase C; Protein Kinase Inhibitors; Receptors, Prostaglandin; Receptors, Prostaglandin E, EP2 Subtype

Prostaglandin F2α analogues are the first-line medication for the treatment of ocular hypertension (OHT), and prostanoid EP2 receptor agonists are under clinical development for this indication. The goal of this study was to investigate the effects of F prostanoid (FP) and EP2 receptor activation on the myofibroblast transition of primary trabecular meshwork (TM) cells, which could be a causal mechanism of TM dysfunction in glaucoma.. Human primary TM cells were treated with either latanoprost or butaprost and TGF-β2. Trabecular meshwork contraction was measured in a three-dimensional (3D) TM cell-populated collagen gel (CPCG) model. Expression of α-smooth muscle actin (α-SMA) and phosphorylation of myosin light chain (MLC) were determined by Western blot. Assembly of actin stress fibers and collagen deposition were evaluated by immunocytochemistry. Involvement of p38, extracellular signal-regulated kinase (ERK), and Rho-associated kinase (ROCK) pathways as well as matrix metalloproteinase activation was tested with specific inhibitors.. In one source of validated adult TM cells, latanoprost induced cell contraction as observed by CPCG surface reduction and increased actin polymerization, α-SMA expression, and MLC phosphorylation, whereas butaprost inhibited TGF-β2-induced CPCG contraction, actin polymerization, and MLC phosphorylation. Both agonists inhibited TGF-β2-dependent collagen deposition. The latanoprost effects were mediated by p38 pathway.. Latanoprost decreased TM collagen accumulation but promoted a contractile phenotype in a source of adult TM cells that could modulate the conventional outflow pathway. In contrast, butaprost attenuated both TM contraction and collagen deposition induced by TGF-β2, thereby inhibiting myofibroblast transition of TM cells. These results open new perspectives for the management of OHT.

Topics: Actins; Adult; Alprostadil; Animals; Antihypertensive Agents; Blotting, Western; Cell Survival; Cells, Cultured; Dinoprost; Glaucoma; Humans; Immunohistochemistry; Latanoprost; Male; Myofibroblasts; Myosin Light Chains; Neuroprotective Agents; Prostaglandins E, Synthetic; Prostaglandins F, Synthetic; Rats; Real-Time Polymerase Chain Reaction; Receptors, Prostaglandin; Receptors, Prostaglandin E, EP2 Subtype; RNA; Signal Transduction; Trabecular Meshwork

The aim of this study was to determine whether the magnitude of the intraocular-pressure (IOP)-lowering response in monkeys to the nonselective prostaglandin (PG)F(2a)-isopropyl ester (ie) can be reproduced by combining other PG-subtype-selective compounds. IOP was lowered by approximately 25% after 4-5 days of topical administration with latanoprost (FP agonist, 1.5 microg, q.d.), bimatoprost (prostamide, whose metabolites have been shown to be FP agonists; 9 microg, q.d.), or travoprost (FP agonist, 1.2 microg, q.d) or the EP2 agonist, butaprost (25 microg, b.i.d.). The EP1 agonist, 17-phenyl trinor (PhT) PGE2 (b.i.d.), and EP3 agonist, sulprostone (b.i.d.), had no IOP-lowering effects. The addition of butaprost, sulprostone (10 microg), or 17PhTPGE2 (25 microg) to latanoprost did not lower IOP more than latanoprost alone. However, treatment with the combination of latanoprost, 17PhTPGE2, butaprost, and sulprostone produced a similar 50-55% reduction in IOP, as did PGF(2)alpha-ie (b.i.d.). In conclusion, latanoprost, travoprost, and bimatoprost produce similar IOP-lowering responses in normotensive monkeys and are most efficacious when administered q.d. pm, compared to b.i.d. The combination of the FP, EP1, EP2, and EP3 agonists used in this study was sufficient to lower IOP by the same magnitude as PGF(2)alpha-ie, suggesting that combining PG-subtype agonists may be a potent antiglaucoma strategy.

Topics: Administration, Topical; Alprostadil; Amides; Animals; Antihypertensive Agents; Bimatoprost; Cloprostenol; Dinoprost; Dinoprostone; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Humans; Intraocular Pressure; Latanoprost; Macaca fascicularis; Male; Ophthalmic Solutions; Prostaglandins F, Synthetic; Receptors, Prostaglandin; Receptors, Prostaglandin E; Tonometry, Ocular; Travoprost

The inflammatory cytokine interleukin-1 (IL-1) decreases mineralisation by immortalized mouse-derived cementoblastic cells (OC-CM cells), whilst various prostanoids, including fluprostenol (flup) increase it. Subtraction hybridisation conducted on flup minus IL-1-treated OC-CM cells revealed that one of the primary response genes preferentially induced by flup is the transcription factor Nur77. The objective of this study was to examine the signal transduction cascades regulating prostanoid induction of Nur77 gene expression in OC-CM cells.. Confluent OC-CM cells were treated with prostaglandin E(2) (PGE(2)), prostaglandin F(2alpha) (PGF(2alpha)), specific activators of the various EP prostanoid receptors and of the FP prostanoid receptor, and direct activators/inhibitors of the cyclic AMP-protein kinase A (PKA), protein kinase C (PKC) and intracellular calcium pathways. Nur77 gene expression was examined by mRNA extraction and Northern blot analysis.. PGE(2) and PGF(2alpha) treatment of OC-CM cells significantly increased Nur77 mRNA expression in a time- and dose-dependent fashion. Both the EP1 prostanoid receptor-specific activator 16,16-dimethyl-PGE(2) and the FP prostanoid receptor-specific activator flup significantly increased Nur77 gene expression by OC-CM cells as compared to vehicle-treated controls. Increase in Nur77 gene expression was also observed when direct activators of the PKA, PKC and intracellular calcium pathways were used to treat OC-CM cells. Direct inhibition of the PKA, PKC and intracellular calcium pathways abrogated Nur77 gene expression induced by OC-CM cell treatment with PGE(2) and PGF(2alpha).. Nur77 is a primary gene expressed by OC-CM cells and its induction appears to be mediated by the PKA, PKC and intracellular calcium pathways. Nur77 may affect expression of downstream target genes in OC-CM cells and partially regulate cementoblast cell function.

Topics: Alprostadil; Animals; Calcium Signaling; Cells, Cultured; Colforsin; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Dental Cementum; Dinoprost; Dinoprostone; Dose-Response Relationship, Drug; Gene Expression Regulation; Mice; Misoprostol; Nuclear Receptor Subfamily 4, Group A, Member 1; Prostaglandins; Prostaglandins F, Synthetic; Protein Kinase C; Receptors, Prostaglandin; Receptors, Prostaglandin E; Signal Transduction; Time Factors

Prostaglandins are bioactive lipids and important mediators of uterine relaxation as well as contraction during pregnancy and labour. E series prostaglandins may directly contract or relax myometrium in a dose-dependent manner, with the relaxatory effects mediated through the prostanoid receptors EP(2) and EP(4). The aim of this study was to evaluate the pharmacological effects of prostaglandin analogues on isolated pregnant rat uterine contractility, at 10(-15) to 10(-9) M concentrations. Uterine strips from rats at 19 days of gestation were set up in organ baths at 37 degrees C, bathed in Krebs buffer and gassed with 95% O(2)/5% CO(2). Spontaneous contractions were recorded via a force transducer. Concentration ranges of 10(-15)-10(-9) M of PGE(2), PGF(2alpha) and a range of prostaglandin analogues were applied non-cumulatively to the tissues. Spontaneous contractions were recorded for 12 min post dose. Amplitude, frequency, baseline tone and percent contractility over 10 min periods were analysed. PGE(2), butaprost, 9-keto fluprostenol, 11-keto fluprostenol, 9-keto fluprostenol isopropyl ester, AL8810 and 15(S)-15-methyl PGE(2) all caused a decrease in percent contractility (P<0.05). These agents, plus Delta(12)PGJ(2) and 9-deoxy-9-methylene-16,16-dimethyl PGE(2), also decreased frequency of contraction (P<0.05). Only PGE(2), PGF(2alpha) and 11-keto fluprostenol decreased baseline tone (P<0.05). The lower concentrations of prostaglandins used here mediated inhibition of spontaneous contractility of pregnant rat myometrium. Use of selective agonists suggested that the prostanoid receptors EP(2) and DP(2) are responsible for this relaxatory effect.

Topics: Alprostadil; Animals; Dinoprost; Dinoprostone; Dose-Response Relationship, Drug; Female; In Vitro Techniques; Pregnancy; Pregnancy, Animal; Prostaglandin D2; Prostaglandins; Prostaglandins F, Synthetic; Rats; Uterine Contraction

The cyclooxygenase-prostanoid pathway regulates myometrial contractility through activation of prostanoid receptors on uterine smooth muscles. However, the possible expression of prostanoid receptors on autonomic nerves cannot be excluded completely. The aim of the present study was to clarify the presence of neural prostanoid receptors on adrenergic nerves in the porcine uterine longitudinal muscle. In [(3)H]-noradrenaline-loaded longitudinal muscle strips of porcine uterus, electrical field stimulation (EFS) evoked [(3)H]-noradrenaline release in a stimulation frequency-dependent manner. The EFS-evoked release was completely abolished in Ca(2+)-free (EGTA, 1mM) incubation medium and by tetrodotoxin or omega-conotoxin GVIA, suggesting that [(3)H]-noradrenaline was released from neural components. The EFS-evoked [(3)H]-noradrenaline release was significantly enhanced by treatment with indomethacin. In the presence of indomethacin, PGE(2) and PGF(2alpha), but not PGD(2), inhibited the EFS-evoked [(3)H]-noradrenaline release. Of synthetic prostanoid receptor agonists examined, both U46619 (TP) and sulprostone (EP(1)/EP(3)) decreased the EFS-evoked [(3)H]-noradrenaline release in a concentration-dependent manner, while fluprostenol (FP), BW245C (DP) and butaprost (EP(2)) were almost ineffective. SQ29548 (TP receptor antagonist) blocked the effect of U46619, but SC19220 (EP(1) receptor antagonist) did not change the inhibition by sulprostone or PGE(2). Double immunofluorescence staining using protein gene product 9.5, tyrosine hydroxylase, EP(3) receptor and TP receptor antibodies suggested the localization of EP(3) or TP receptors on adrenergic nerves in the porcine uterus. These results indicated that neural EP(3) and TP receptors are present on adrenergic nerves of the porcine uterine longitudinal muscle. Endogenous prostanoid produced by cyclooxygenase can regulate noradrenaline release in an inhibitory manner through activation of these neural prostanoid receptors.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Alprostadil; Animals; Dinoprost; Dinoprostone; Electric Stimulation; Female; In Vitro Techniques; Microscopy, Confocal; Microscopy, Fluorescence; Myometrium; Neurons; Norepinephrine; Prostaglandin D2; Prostaglandins; Prostaglandins F, Synthetic; Receptors, Androgen; Receptors, Prostaglandin; Swine

1. Using gene chip technology, we first identified that PGF(2alpha) (FP agonist) and Butaprost (EP(2) agonist) induced about a five-fold upregulation of Nur77 mRNA expression in hFP-HEK 293/EBNA and hEP(2)-HEK293/EBNA cells. Northern Blot analysis revealed that PGF(2alpha)- and Butaprost-induced upregulation of Nur77 expression are dose- and time-dependent. 2. Both PGF(2alpha) and Butaprost upregulated Nur77 gene expression through the protein kinase C (PKC) pathway. These data are the first showing a link between EP(2) receptor stimulation and protein kinase C activation. Calcineurin was found to be involved downstream of the PKC pathway in PGF(2alpha)-induced Nur77 expression, but not in Butaprost-induced Nur77 expression. 3. We also used Nur77 as a marker gene to compare the effects of PGF(2alpha), Butaprost, and Bimatoprost (a prostamide) on Nur77 expression in human primary trabecular meshwork and ciliary smooth muscle (SM) cells, which are target cells for antiglaucoma drugs. The results showed that PGF(2alpha) and Butaprost, but not Bimatoprost, induced upregulation of Nur77 expression in human TM cells. PGF(2alpha), but not Bimatoprost, dramatically induced upregulation of Nur77 mRNA expression in human ciliary SM cells, whereas Butaprost slightly upregulated Nur77 mRNA expression in SM cells. 4. Nur77 promoter deletion analysis indicated that PGF(2alpha), but not Bimatoprost, activated Nur77 promoter-luciferase reporter in hFP-HEK 293/EBNA cells. Butaprost was less efficacious in inducing Nur77 promoter-luciferase reporter activity in hEP(2)-HEK293/EBNA cells relative to PGF(2alpha) in the comparable assay. The data for Nur77 promoter functional analysis were matched to the Northern blot analysis. 5. It appears that PGF(2alpha) and Butaprost activate Nur77 transcription mechanisms through the activation of FP and EP(2) receptor-coupled signaling pathways, whereas Bimatoprost stimulates neither FP nor EP(2) receptors.

Topics: Alprostadil; Amides; Bimatoprost; Cell Line; Ciliary Body; Cloprostenol; Dinoprost; DNA-Binding Proteins; Epstein-Barr Virus Nuclear Antigens; Humans; Immunoblotting; Kinetics; Lipids; Luciferases; Nuclear Receptor Subfamily 4, Group A, Member 1; Promoter Regions, Genetic; Protein Kinase C; Receptors, Cytoplasmic and Nuclear; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Steroid; RNA; Trabecular Meshwork; Transcription Factors; Transcription, Genetic; Transfection; Up-Regulation

Connective tissue growth factor (CTGF) and Cyr61 (cysteine-rich angiogenic protein 61) are members of the CCN gene family that encode multifunctional, extracellular matrix-associated signaling proteins. Because the mechanism of action of certain anti-glaucoma drugs involves extracellular matrix remodeling of ocular ciliary muscle, with a resultant increase in drainage of aqueous humor from the eye, we compared the effects of three pharmacologically distinct ocular hypotensive agents on Cyr61 and CTGF gene expression. Thus, prostaglandin F2alpha (PGF2alpha) (FP receptor agonist), Butaprost (EP2 receptor agonist), and Bimatoprost (a prostamide) were compared. Using Affymetrix gene chip technology, we first identified that PGF2alpha dramatically up-regulated Cyr61 and CTGF mRNA expression in HEK 293/EBNA cells (hFP-HEK 293/EBNA). Northern blot further confirmed the Cyr61 and CTGF up-regulation is in a dose- and time-dependent manner. PGF2alpha-induced up-regulation of Cyr61 appeared to exclusively involve the Rho pathway, and up-regulation of CTGF was via multiple intracellular pathways. Because prostamide receptors are, to date, defined only at the pharmacological level, Bimatoprost effects on Cyr61 and CTGF were studied in the isolated feline iris sphincter preparation, a tissue highly responsive to prostamides. Both PGF2alpha and Bimatoprost up-regulated Cyr61 mRNA expression in the cat iris tissue. Only PGF2alpha up-regulated CTGF mRNA expression in the cat iris. Therefore, PGF2alpha and Bimatoprost appear to interact with different receptors populations in the cat iris, according to their markedly different effects on CTGF. Activation of prostaglandin EP2 receptors (Gs-coupled) also up-regulated Cyr61 but not CTGF mRNA expression in the isolated cat iris. Similar data were observed in human primary ciliary smooth muscle cells. Thus, despite quite different signal transduction pathways, FP receptor stimulation up-regulates CTGF and Cyr61. The prostamide analog Bimatoprost and an EP2-selective agonist affects only Cyr61.

Topics: Alprostadil; Amides; Animals; Bimatoprost; Cats; Cell Line; Cells, Cultured; Ciliary Body; Cloprostenol; Connective Tissue Growth Factor; Cysteine-Rich Protein 61; Dinoprost; Gene Expression; Glaucoma; Humans; Immediate-Early Proteins; In Vitro Techniques; Intercellular Signaling Peptides and Proteins; Iris; Kinetics; Lipids; Oligonucleotide Array Sequence Analysis; Promoter Regions, Genetic; RNA, Messenger; Signal Transduction; Trabecular Meshwork; Up-Regulation

Although the role of PGE2 in maintaining ductus arteriosus (DA) patency is well established, the specific PGE2 receptor subtype(s) (EP) involved have not been clearly identified. We used late gestation fetal and neonatal lambs to study developmental regulation of EP receptors. In the fetal DA, radioligand binding and RT-PCR assays virtually failed to detect EP1 but detected EP2, EP3D, and EP4 receptors in equivalent proportions. In the newborn lamb, DA total density was one-third of that found in the fetus and only EP2 was detected. Stimulation of EP2 and EP4 increased cAMP formation and was associated with DA relaxation. Though stimulation of EP3 inhibited cAMP formation, it surprisingly relaxed the fetal DA both in vitro and in vivo. This EP3-induced relaxation was specifically diminished by the ATP-sensitive K(+) (K(ATP)) channel blocker glibenclamide. In conclusion, PGE2 dilates the late gestation fetal DA through pathways that involve either cAMP (EP2 and EP4) or K(ATP) channels (EP3). The loss of EP3 and EP4 receptors in the newborn DA is consistent with its decreased responsiveness to PGE2.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Adenosine Triphosphate; Alprostadil; Animals; Animals, Newborn; Anti-Arrhythmia Agents; Anti-Ulcer Agents; Binding, Competitive; Biphenyl Compounds; Colforsin; Dinoprost; Ductus Arteriosus; Female; Fetus; Polymerase Chain Reaction; Potassium Channels; Pregnancy; Prostaglandin Antagonists; Prostaglandins E, Synthetic; Radioligand Assay; Receptors, Prostaglandin E; Sheep; Tritium; Vasoconstriction; Xanthenes; Xanthones

1. We studied the effects of intracerebroventricular (i.c.v.) administration of prostaglandin E2 (PGE2) and its receptor subtype ligands on plasma levels of catecholamines in urethane-anaesthetized rats. 2. Administration of PGE2 (0.15, 0.3 and 1.5 nmol per animal, i.c.v.) dose-dependently elevated plasma levels of noradrenaline (NA), while the levels of adrenaline were not affected. 3. Administration of sulprostone (EP3/EP1 agonist) and misoprostol (EP3/EP2 agonist) effectively elevated plasma NA levels in a dose-dependent manner (0.1, 0.3, and 1.0 nmol per animal). Butaprost (EP2 agonist) (0.3, 1.0 and 3.0 nmol per animal) was without effect. 17-Phenyl-omega-trinor PGE2 (EP1/EP3 agonist) effectively elevated plasma NA levels only at its highest dose (1.0 nmol per animal), but this elevation was not attenuated by pretreatment with SC-19220 (selective EP1 antagonist) (20 nmol per animal, i.c.v.). 4. The potency of these test agents in elevating plasma levels of NA was as follows; misoprostol > sulprostone > PGE2 > > 17-phenyl-omega-trinor PGE2 > > > butaprost. These results suggest that activation of central prostanoid EP3-receptors induces central sympathetic outflow in rats.

Topics: Abortifacient Agents, Nonsteroidal; Alprostadil; Anesthetics, Intravenous; Animals; Brain; Dibenz(b,f)(1,4)oxazepine-10(11H)-carboxylic acid, 8-chloro-, 2-acetylhydrazide; Dinoprost; Dinoprostone; Dose-Response Relationship, Drug; Injections, Intraventricular; Male; Misoprostol; Norepinephrine; Prostaglandin Antagonists; Rats; Rats, Wistar; Receptors, Prostaglandin E; Urethane

1. We have shown that intracisternal (i.c.) administration of interleukin-1 beta (IL-1 beta) attenuates naloxone-precipitated withdrawal jumps in morphine-dependent mice, and the effect was partly mediated by the corticotropin-releasing factor. To elucidate further other possible mechanisms involved in the inhibitory effect of IL-1 beta on morphine withdrawal jumping behaviour, in this study, we examined the involvement of the prostaglandin-synthesis pathway, because prostaglandins have been shown to mediate the several central effects of IL-1. Furthermore, we examined the effects of subtype-selective prostaglandin receptor agonists on morphine withdrawal jumping behaviour. 2. Mice were rendered morphine-dependent by subcutaneous implantation of a pellet containing 11.5 +/- 0.3 mg morphine hydrochloride for 48 h. Morphine withdrawal syndromes were precipitated by intraperitoneal (i.p.) injection of naloxone (10 mg kg-1). The degree of physical dependence on morphine was estimated by counting the number of jumps, one of the typical withdrawal signs in mice, for 40 min. 3. The inhibitory effect of IL-1 beta (1 ng/mouse) administered intracisternally 30 min before naloxone (10 mg kg-1, i.p.) was significantly blocked by pretreatment with sodium salicylate (a cyclo-oxygenase inhibitor, 10 ng or 30 ng/mouse) administered intracisternally 15 min before IL-1 beta, while i.c. administration of sodium salicylate alone (3 ng, 10 ng or 30 ng/mouse) followed by i.c. administration of vehicle instead of IL-1 beta did not significantly change the number of jumps precipitated by naloxone. 4. Intracisternal administration of M&B28,767 (an EP3-receptor agonist, 1 fg-30 ng/mouse) and sulprostone (an EP1/EP3-receptor agonist, 10 fg-100 ng/mouse) 30 min before naloxone (10 mg kg,-1 i.p.) attenuated withdrawal jumps with a U-shaped dose-response, reaching a peak at 10 pg/mouse and 100 pg/mouse, respectively. On the other hand, i.c. administration of iloprost (an EP1/IP-receptor agonist, 10 fg-100 ng/mouse), butaprost (an EP2-receptor agonist, 10 fg-100 ng/mouse) or prostaglandin F2 alpha (a FP-receptor agonist, 10 fg-100 ng/mouse) 30 min before naloxone (10 mg kg-1, i.p.) did not significantly change the number of jumps precipitated by naloxone. 5. These results indicate that the prostaglandin-synthesis pathway is, at least in part, involved in the inhibitory effect of IL-1 beta on naloxone-precipitated withdrawal jumps in morphine-dependent mice, and that the prostaglandin s

Topics: Alprostadil; Analgesics, Opioid; Animals; Behavior, Animal; Dinoprost; Dinoprostone; Interleukin-1; Male; Mice; Mice, Inbred Strains; Morphine; Naloxone; Prostaglandins; Receptors, Prostaglandin E; Sodium Salicylate; Stimulation, Chemical; Substance Withdrawal Syndrome; Substance-Related Disorders