dinoprost and fluprostenol

Topics: Animals; Diestrus; Dinoprost; Embryo Transfer; Estrus; Estrus Synchronization; Female; Horses; Luteolysis; Luteolytic Agents; Ovulation; Pregnancy; Progesterone; Prostaglandins; Prostaglandins F; Prostaglandins F, Synthetic

Topics: Abortion, Induced; Animals; Animals, Domestic; Cattle; Cloprostenol; Dinoprost; Female; Goats; Horses; Luteolytic Agents; Pregnancy; Prostaglandins; Prostaglandins F; Prostaglandins F, Synthetic; Sheep; Swine

6-Hydroxydopamine (6-OHDA) is a neurotoxin that destroy dopaminergic neurons and widely used to establish animal models of Parkinson's disease. Prostaglandins (PGs) are involved in various cellular processes, including the damage and repair of neuronal cells. However, the function of PGF

Topics: Adrenergic Agents; Cell Line, Tumor; Dinoprost; Dose-Response Relationship, Drug; Humans; MAP Kinase Signaling System; Neuroprotection; NF-E2-Related Factor 2; Oxidopamine; Prostaglandins F, Synthetic; Receptors, Prostaglandin

Macrophages are the effector immune cells with plasticity to differentiate as M1 (classically activated) and M2 (alternatively activated) phenotypes. Prostaglandins (PGs) have various important roles and are involved in the regulation of macrophage activation. However, the role of PGF

Topics: Animals; Cell Nucleus; Dinoprost; I-kappa B Kinase; Interferon-gamma; Interleukin-10; Lipopolysaccharides; Macrophage Activation; Macrophages; Mice; Prostaglandins F, Synthetic; RAW 264.7 Cells; Receptors, Prostaglandin; Signal Transduction; Thiophenes; Transcription Factor RelA

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

The endometrium of domestic animals has a remarkable capacity to self-repair. Prostaglandin F

Topics: Animals; Cattle; Cells, Cultured; Connective Tissue Growth Factor; Dinoprost; Endometrium; Epithelial Cells; Female; Intercellular Signaling Peptides and Proteins; Interleukin-8; Luteolytic Agents; Prostaglandin-Endoperoxide Synthases; Prostaglandins F, Synthetic; Protein Kinase C; Receptors, Prostaglandin; Signal Transduction; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A

The endometrium of domestic animals undergoes regular periods of regeneration and degeneration and exhibits a remarkable capacity for self-repair during the oestrous cycle. The endometrial growth pattern is also observed during in the implantation period and early pregnancy, but the mechanism underlying endometrial growth in these processes remains unclear. A positive correlation between endometrial growth in these processes and prostaglandin (PG) F

Topics: Animals; Caspase 3; Cattle; Cell Proliferation; Cells, Cultured; Connective Tissue Growth Factor; Dinoprost; Endometrium; Female; Fibroblast Growth Factor 2; Interleukin-8; Matrix Metalloproteinase 2; Prostaglandins F, Synthetic; Receptors, Prostaglandin; Signal Transduction; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A

Selective activation or blockade of the prostaglandin (PG) F2α receptor (FP receptor) affects ectopic endometrial tissue growth and endometriosis development.. FP receptor antagonists might represent a promising approach for the treatment of peritoneal endometriosis.. Eutopic and ectopic endometrium from women with endometriosis exhibit higher expression of key enzymes involved in the PGF2α biosynthetic pathway. It has also been shown that the PGF2α-FP receptor interaction induces angiogenesis in human endometrial adenocarcinoma.. For this study, a mouse model of endometriosis was developed by inoculating human endometrial biopsies into the peritoneal cavity of nude mouse (n = 15). Mice were treated with AL8810 (FP receptor antagonist), Fluprostenol (FP receptor agonist) or PBS. Endometriosis-like lesions were collected and analysed for set of markers for angiogenesis, tissue remodelling, apoptosis, cell proliferation and capillary formation using qPCR and immunohistochemistry.. We found that selective inhibition of the FP receptor with a specific antagonist, AL8810, led to a significant decline in the number (P < 0.01) and size of endometriosis-like lesions (P < 0.001), down-regulated the expression of key mediators of tissue remodelling (MMP9, P < 0.05) and angiogenesis (VEGF, P < 0.01) and up-regulated the pro-apoptotic factor (Bax, P < 0.01) as compared with controls. Immunohistochemical analyses further showed a marked decrease in cell proliferation and capillary formation in endometrial implants from AL8810-treated mice, as determined by proliferating cell nuclear antigen (PCNA) and von Willebrand factor (vWF) immunostaining, respectively. Moreover, Fluprostenol, a selective FP receptor agonist, showed the opposite effects.. We carried out this study in nude mice, which have low levels of endogenous estrogens which may affect the lesion growth. Caution is required when interpreting these results to women.. This study extends the role of PG signalling in endometriosis pathogenesis and points towards the possible relevance of selective FP receptor antagonism as a targeted treatment for endometriosis.. Not Applicable.. This work was supported by grant MOP-123259 to the late Dr Ali Akoum from the Canadian Institutes for Health Research. The authors have no conflict of interest.

Topics: Animals; Apoptosis; Dinoprost; Dinoprostone; Disease Models, Animal; Disease Progression; Endometriosis; Female; Humans; Luteolytic Agents; Mice; Mice, Nude; Prostaglandins F, Synthetic; Xenograft Model Antitumor Assays

Prostaglandin (PG) F(2α) suppresses adipocyte differentiation by inhibiting the function of peroxisome proliferator-activated receptor γ. In this study, we identified a novel suppression mechanism, operating in the early phase of adipogenesis, that increased the production of anti-adipogenic PGF(2α) and PGE(2) by enhancing cyclooxygenase (COX) 2 expression through the PGF(2α) -activated FP receptor/extracellular-signal-regulated kinase (ERK)/cyclic AMP response element binding protein (CREB) cascade. COX-2 expression was enhanced with a peak at 1 h for the mRNA level and at 3 h for the protein level after the addition of Fluprostenol, an FP receptor agonist. The Fluprostenol-derived elevation of COX-2 expression was suppressed by the co-treatment with an FP receptor antagonist, AL8810, with a mitogen-activated protein kinase (MEK; ERK kinase) inhibitor, PD98059. ERK was phosphorylated within 10 min after the addition of Fluprostenol, and its phosphorylation was inhibited by the co-treatment with AL8810 or PD98059. Moreover, FP receptor mediated activation of the MEK/ERK cascade and COX-2 expression increased the production of PGF(2α) and PGE(2) . An FP receptor antagonist and each inhibitor for MEK and COX-2 suppressed the PGF(2α) -derived induction of synthesis of these PGs. Furthermore, promoter-luciferase and chromatin immunoprecipitation assays demonstrated that PGF(2α) -derived COX-2 expression was activated through binding of CREB to the promoter region of the COX-2 gene in 3T3-L1 cells. These results indicate that PGF(2α) suppresses the progression of the early phase of adipogenesis by enhancing the binding of CREB to the COX-2 promoter via FP receptor activated MEK/ERK cascade. Thus, PGF(2α) forms a positive feedback loop that coordinately suppresses the early phase of adipogenesis through the increased production of anti-adipogenic PGF(2α) and PGE(2) .

Topics: 3T3-L1 Cells; Adipogenesis; Animals; Cyclic AMP Response Element-Binding Protein; Cyclooxygenase 2; Dinoprost; Dinoprostone; Extracellular Signal-Regulated MAP Kinases; Feedback; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinase Kinases; PPAR gamma; Prostaglandins F, Synthetic; Receptors, Prostaglandin; Signal Transduction

FP-Class prostaglandin analogs have demonstrated utility for the treatment of glaucoma and ocular hypertension. A series of novel FP prostaglandin analogs was designed to optimize topical ocular activity and reduce ocular side-effects by replacing 13-carbon with oxygen. A facile synthesis was successfully developed for synthesis of the 13-oxa prostaglandins from the commercially available Corey aldehyde benzoate. Among the compounds synthesized, AL-16082 was the most potent prostaglandin FP agonist in vitro. In a prostaglandin FP receptor-linked second-messenger assay, phosphoinositide (PI) turnover, it exhibited a potency value (EC(50)) of 1.9 nM (78% max. response relative to fluprostenol). The isopropyl ester of AL-16082, compound AL-16049, significantly lowered intraocular pressure (IOP) in the ocular hypertensive monkey eyes by 30%. In the study of acute ocular irritation response in New Zealand albino rabbits, AL-16049 produced lower incidence of hyperemia, swelling, and discharge than PGF(2alpha) (1 microg), and a similar incidence of hyperemia, swelling, and discharge to latanoprost (1.8 microg). AL-16049 also produced no signs of ocular irritation or discomfort in the cat at the doses evaluated.

Topics: Administration, Topical; Animals; Cats; Dinoprost; Drug Discovery; Eye Diseases; Glaucoma; Haplorhini; Hypertension; Intraocular Pressure; Prostaglandins F, Synthetic; Prostaglandins, Synthetic; Rabbits; Structure-Activity Relationship

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

Prostaglandin F2alpha (PGF2alpha) increases reactive oxygen species (ROS) and induces vascular smooth muscle cell (VSMC) hypertrophy by largely unknown mechanism(s). To investigate the signaling events governing PGF2alpha-induced VSMC hypertrophy we examined the ability of the PGF2alpha analog, fluprostenol to elicit phosphorylation of Akt, the mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase (p70S6k), glycogen synthase kinase-3beta (GSK-3beta), phosphatase and tensin homolog (PTEN), extracellular signal-regulated kinase 1/2 (ERK1/2) and Jun N-terminal kinase (JNK) in growth arrested A7r5 VSMC. Fluprostenol-induced hypertrophy was associated with increased ROS, mTOR translocation from the nucleus to the cytoplasm, along with Akt, mTOR, GSK-3beta, PTEN and ERK1/2 but not JNK phosphorylation. Whereas inhibition of phosphatidylinositol 3-kinase (PI3K) by LY-294002 blocked fluprostenol-induced changes in total protein content, pre-treatment with rapamycin or with the MEK1/2 inhibitor U0126 did not. Taken together, these findings suggest that fluprostenol-induced changes in A7r5 hypertrophy involve mTOR translocation and occur through PI3K-dependent mechanisms.

Topics: Animals; Blotting, Western; Cell Line; Dinoprost; Fluorescent Antibody Technique; MAP Kinase Signaling System; Microscopy, Fluorescence; Muscle, Smooth, Vascular; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Prostaglandins F, Synthetic; Protein Kinases; PTEN Phosphohydrolase; Rats; Reactive Oxygen Species; Ribosomal Protein S6 Kinases, 70-kDa; TOR Serine-Threonine Kinases

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

Prostanoids that activate protein kinase C signaling are potent anabolic stimulators of cementoblastic OCCM cells. Using cDNA subtractive hybridization, we identified early growth response gene-1 (egr1) as a prostanoid-induced gene. Egr1, a zinc-finger transcription factor expressed during tooth development, regulates cell growth and differentiation. We hypothesize that Egr1 may mediate part of the prostanoid-induced anabolic effect in cementoblasts. Our objective was to characterize prostanoid-induced egr1 gene expression in OCCM cells.. Total RNA and proteins were assayed by northern blot and western immunoblot assays.. Prostaglandin E2-, prostaglandin F2alpha- and fluprostenol-induced egr1 mRNA levels peaked at 0.5 h and returned to baseline by 4 h. Prostaglandin F2alpha and fluprostenol more potently induced egr1 compared with prostaglandin E2. The phorbol ester, phorbol 12-myristate 13-acetate, which activates protein kinase C signaling, induced egr1 mRNA levels 66-fold over the control, whereas forskolin (a cAMP-protein kinase A activator) and ionomycin (a calcium activator) had no effect. Protein kinase C inhibition significantly inhibited prostaglandin E2-, prostaglandin F2alpha- and fluprostenol-induced egr1 mRNA levels. Finally, prostanoids maximally induced Egr1 protein at 1 h.. egr1 is a primary response gene induced by prostaglandin E2, prostaglandin F2alpha and fluprostenol in OCCM cells through protein kinase C signaling, suggesting that Egr1 may be a key mediator of anabolic responses in cementoblasts. Cementum is vital for periodontal organ maintenance and regeneration. Periodontal ligament fibers (Sharpey's fibers) insert into bone and cementum, thereby supporting the tooth in the alveolus (1). If the periodontal organ is lost, its regeneration requires cementoblast differentiation in order to form new cementum for periodontal ligament fiber insertion. Early attempts to regenerate cementum have proven difficult and rarely generate sufficient tissue (2). A better understanding of the molecular and cellular regulators that promote cementoblast differentiation is critical for developing targeted periodontal regeneration.

Topics: Animals; Blotting, Northern; Blotting, Western; Carcinogens; Cell Line; Colforsin; Dental Cementum; Dinoprost; Dinoprostone; Early Growth Response Protein 1; Enzyme Activators; Gene Expression Regulation; Ionomycin; Ionophores; Mice; Prostaglandins; Prostaglandins F, Synthetic; Protein Kinase C; RNA, Messenger; Signal Transduction; Tetradecanoylphorbol Acetate; Time Factors; Zinc Fingers

Parathyroid hormone (PTH) regulates osteoblast function by binding to the PTH receptor 1 (PTHR1) to activate downstream signaling to induce expression of primary response genes (PRGs), which affect various aspects of the osteoblast phenotype. We previously identified PTH-induced PRGs in MC3T3-E1 cells, including mitogen-activated protein kinase (MAPK) phosphatase 1 (mkp1), which dephosphorylates members of the MAPK family. The aim of this study was to explore the molecular mechanisms of PTH's induction of mkp1 in primary mouse osteoblasts.. Northern and Western analyses were used to determine mkp1 mRNA and protein expression. In vivo experiments were also performed to determine PTH's effect on mkp1 in mouse calvariae and long bones.. A total of 10 nM PTH and PTH-related protein (PTHrP) maximally induced mkp1 mRNA levels after 1 hour in osteoblasts. PTH also increased mkp1 protein expression, and induced mkp1 mRNA independent of new protein synthesis. PTHR1 triggers protein kinase A (PKA), PKC, and calcium pathways. Although PKA and PKC agonists induced mkp1 mRNA levels, only cyclic adenosine 3':5'-monophosphate (cAMP)-PKA inhibition blocked PTH-induced mkp1 mRNA levels. These data suggest that PTH-induced mkp1 mRNA levels are primarily mediated through the cAMP-PKA pathway. Further, prostaglandin E2 (PGE2), which activates cAMP-PKA and PKC, induced mkp1 mRNA to a greater extent than PGF2alpha and fluprostenol, which activate PKC signaling only. Finally, PTH maximally induced mkp1 mRNA levels in mouse calvariae and long bones in vivo at 0.5 hours.. mkp1's in vitro and in vivo induction in PTH-target tissues suggests its involvement in some of the effects of PTH on osteoblast function. mkp1 may be an important target gene in the anabolic effect of PTH on osteoblasts.

Topics: Animals; Bone and Bones; Calcium Signaling; Cells, Cultured; Cyclic AMP-Dependent Protein Kinases; Dinoprost; Dinoprostone; Dual Specificity Phosphatase 1; Enzyme Induction; Gene Targeting; Male; Mice; Mice, Inbred Strains; Osteoblasts; Parathyroid Hormone; Parathyroid Hormone-Related Protein; Prostaglandins F, Synthetic; Protein Kinase C; Protein Phosphatase 1; Protein Tyrosine Phosphatases; RNA, Messenger; Signal Transduction; Skull; Time Factors

Cementum is a key component of a functional periodontal organ. However, regenerating lost cementum is difficult and often incomplete. Identifying molecular mediators of cementoblast differentiation and function should lead to better targeted treatment for periodontitis. Prostaglandins increase mineralization of murine cementoblastic OCCM cells and alveolar bone formation, whereas the cytokine interleukin-1 (IL-1) inhibits alveolar bone formation. We hypothesized that differentially induced primary genes in OCCM cells may mediate anabolic and catabolic responses. Our objective was to identify primary genes differentially induced by the synthetic prostanoid fluprostenol and IL-1 in cementoblastic cells.. Confluent OCCM cells were pretreated with the protein synthesis inhibitor cycloheximide followed by fluprostenol or IL-1 for 1.5 hours. cDNA generated from each group was used for cDNA subtraction hybridization to identify differentially induced genes. Preferential gene induction was verified by Northern blot analysis.. Thirteen fluprostenol- and seven IL-1-regulated genes were identified. Among the fluprostenol-induced genes was mitogen-activated protein (MAP) kinase phosphatase 1 (MKP1), a negative regulator of MAP kinase signaling. To verify the cDNA subtraction hybridization results, OCCM cells were treated with fluprostenol or prostaglandin F2 (PGF2), and MKP1 mRNA levels were determined. The 0.001 to 1 microM fluprostenol and 0.01 to 1 microM PGF2 significantly induced MKP1 mRNA levels, which peaked at 1 hour of treatment and returned to baseline at 2 hours.. Fluprostenol enhanced, whereas IL-1 inhibited, OCCM mineralization. Using cDNA subtraction hybridization, we identified primary genes that correlate with the observed anabolic and catabolic responses. These findings further our understanding of cementoblast function and suggest that differentially induced genes may mediate cementum formation and resorption.

Topics: Animals; Blotting, Northern; Cell Cycle Proteins; Cell Line, Transformed; Dental Cementum; Dinoprost; DNA, Complementary; Dual Specificity Phosphatase 1; Enzyme Induction; Gene Expression Profiling; Gene Expression Regulation; Immediate-Early Proteins; Interleukin-1; Mice; Nucleic Acid Hybridization; Phosphoprotein Phosphatases; Prostaglandins F, Synthetic; Protein Phosphatase 1; Protein Tyrosine Phosphatases; RNA, Messenger; Tooth Calcification; Transcriptional Activation

We have previously reported that prostaglandin F(2alpha) (PGF(2alpha)) and its selective agonist fluprostenol increase basic fibroblast growth factor (FGF-2) mRNA and protein production in osteoblastic Py1a cells. The present report extends our previous studies by showing that Py1a cells express FGF receptor-2 (FGFR2) and that treatment with PGF(2alpha) or fluprostenol decreases FGFR2 mRNA. We have used confocal and electron microscopy to show that, under PGF(2alpha) stimulation, FGF-2 and FGFR2 proteins accumulate near the nuclear envelope and colocalize in the nucleus of Py1a cells. Pre-treatment with cycloheximide blocks nuclear labelling for FGF-2 in response to PGF(2alpha). Treatment with SU5402 does not block prostaglandin-mediated nuclear internalization of FGF-2 or FGFR2. Various effectors have been used to investigate the signal transduction pathway. In particular, pre-treatment with phorbol 12-myristate 13-acetate (PMA) prevents the nuclear accumulation of FGF-2 and FGFR2 in response to PGF(2alpha). Similar results are obtained by pre-treatment with the protein kinase C (PKC) inhibitor H-7. In addition, cells treated with PGF(2alpha) exhibit increased nuclear labelling for the mitogen-activated protein kinase (MAPK), p44/ERK2. Pre-treatment with PMA blocks prostaglandin-induced ERK2 nuclear labelling, as confirmed by Western blot analysis. We conclude that PGF(2alpha) stimulates nuclear translocation of FGF-2 and FGFR2 by a PKC-dependent pathway; we also suggest an involvement of MAPK/ERK2 in this process.

Topics: Animals; Blotting, Western; Cell Line, Transformed; Cell Nucleus; Dinoprost; Fibroblast Growth Factor 2; Fluorescent Antibody Technique, Indirect; Gene Expression Regulation; Immunohistochemistry; Microscopy, Confocal; Microscopy, Immunoelectron; Mitogen-Activated Protein Kinase 3; Nuclear Envelope; Osteoblasts; Prostaglandins; Prostaglandins F, Synthetic; Rats; Receptor Protein-Tyrosine Kinases; Receptor, Fibroblast Growth Factor, Type 2; Receptors, Fibroblast Growth Factor; RNA, Messenger

The prostaglandins (PG) E(2) and PGF(2alpha) are important cytokines in periodontal physiology and pathology. PGE(2) and PGF(2alpha) alter cell function by binding and activating the plasmamembrane G-protein-coupled PG receptors. In this study, we examined the PGE(2) and PGF(2alpha) effects on the immortalized cementoblastic OCCM cells.. Confluent OCCM cells were treated with PGE(2), PGF(2alpha), specific activators/inhibitors of the EP prostanoid receptors, a specific activator of the FP prostanoid receptor, and direct activators/inhibitors of the protein kinase C (PKC) signaling pathway. Mineral nodule formation was assessed by the von Kossa stain.. PGE(2) and PGF(2alpha) significantly increased mineralization of OCCM cells. The EP1 and EP3 PG receptor activators 16,16-dimethyl-prostaglandin E(2) and sulprostone, also increased mineralization. In contrast, specific activators of the EP2 or the EP2/EP3/EP4 receptors did not have any effect. Fluprostenol, a specific activator of the FP receptor, significantly increased mineralization of OCCM cells. FP and EP (1 or 3) receptors signal through activation of the protein kinase C (PKC) pathway. Indeed, phorbol 12-myristate 13-acetate (PMA), a direct activator of the PKC pathway, significantly increase OCCM mineralization, while pre-treatment of OCCM cells with the PKC inhibitor GF109203x (bisindolylmaleimide) significantly decreased mineralization.. We conclude that PGE(2) and PGF(2alpha) exert an anabolic effect on OCCM mineralization through activation of PKC signaling.

Topics: Calcification, Physiologic; Cell Line, Transformed; Dental Cementum; Dinoprost; Dinoprostone; Humans; MAP Kinase Signaling System; Prostaglandins F, Synthetic; Receptors, Prostaglandin; Tetradecanoylphorbol Acetate

Cyclooxygenase-2 may play a role in resolution of carrageenan-induced pleurisy in rats by generating anti-inflammatory prostanoids. Here, we show exudate prostaglandin F2alpha concentrations rise during resolution of this model. These were reduced by the selective cyclooxygenase-2 inhibitor NS-398, which exacerbated inflammation. Concomitant treatment with NS-398 and the synthetic FP receptor agonist fluprostenol reversed this exacerbation. This suggests prostaglandin F2alpha produced by cyclooxygenase-2 contributes to resolution of this inflammatory reaction.

Topics: Analysis of Variance; Animals; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dinoprost; Inflammation; Nitrobenzenes; Pleurisy; Prostaglandins F, Synthetic; Rats; Rats, Wistar; Receptors, Prostaglandin; Sulfonamides

The pharmacological properties of [(3)H]-prostaglandin E(2) ([(3)H]-PGE(2)) binding to washed homogenates of hamster uterus were determined. Scatchard analysis of competition data yielded dissociation constants (K(d)s) of 30.9 +/- 5.6 nM (n = 3) and apparent receptor density (B(max)) of 25.25 +/- 1.89 pmol g(-1) wet weight tissue (74 +/- 8% specific binding). Competition studies yielded the following affinity parameters (K(i)) for various prostanoids: GR63799X = 13 4 nM; PGE(2) = 17 +/- 3 nM; sulprostone = 64 +/- 5 nM; enprostil = 67 +/- 3 nM; misoprostol = 124 +/- 15 nM; cloprostenol = 187 +/- 33 nM; carba-prostacyclin = 260 +/- 167 nM; iloprost = 555 +/- 162 nM; PGF(2 alpha) = 767 +/- 73 nM; PGD(2) > 3560 nM; fluprostenol = 11 790 +/- 2776 nM; RS93520 = 21 558 +/- 14 228 nM. These data closely matched the pharmacological profile of previously described EP(3) receptors such as in bovine corpus luteum (BCLM) and the cloned mammalian EP(3) receptors. The high correlation between the current hamster uterus pharmacology data vs the EP(3) receptor binding in BCLM (r = 0.94; P < 0.0001), vs cloned human EP(3) receptor (r = 0.94, P < 0.0001), vs the cloned mouse EP(3) receptor binding (r = 0.78; P < 0.002), vs cloned rat EP(3) receptor (r = 0.9, P < 0.0004), and vs EP(3) receptor-mediated functional responses (r = 0.72, P < 0.02) substantiated the conclusion that the hamster uterus contains EP(3) receptor binding sites.

Topics: Animals; Binding Sites; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cattle; Cloprostenol; Cricetinae; Dinoprost; Dinoprostone; Enprostil; Epoprostenol; Fatty Acids, Unsaturated; Female; Hydantoins; Hydrazines; Iloprost; Latanoprost; Misoprostol; Prostaglandins; Prostaglandins E, Synthetic; Prostaglandins F, Synthetic; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP3 Subtype; Tritium; Uterus

We have investigated the actions of various prostanoid receptor agonists on an isolated preparation of the ferret cervical vagus using a grease-gap extracellular recording technique. The potency ranking for depolarization was BW245C (5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl) hydantoin; DP-selective, EC50=0.14 microM)>prostaglandin E2 (nonselective EP agonist)>U-46619 (11alpha, 9alpha-epoxymethano-15S-hydroxyprosta-5Z,13E-dienoic acid; TP agonist)>prostaglandin F2alpha (FP receptor agonist). Sulprostone (EP1/EP3-selective), fluprostenol (FP-selective) and cicaprost and iloprost (both IP-selective) had minimal effects. It is likely that DP, EP2/EP4 and TP receptors are present on the vagal fibres of the ferret.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Biguanides; Dinoprost; Dinoprostone; Dose-Response Relationship, Drug; Electrophysiology; Epoprostenol; Ferrets; Hydantoins; Iloprost; In Vitro Techniques; Male; Prostaglandins; Prostaglandins F, Synthetic; Serotonin; Vagus Nerve

This study was undertaken to investigate the vascular actions (contraction and relaxation) of the F(2)-isoprostane metabolites 15-keto-15-F(2t)-IsoP, 2,3-dinor-15-F(2t)-IsoP, and 2,3-dinor-5,6-dihydro -15-F(2t)-IsoP in comparison with 15-F(2t)-IsoP on the rat thoracic aorta. 15-keto-15-F(2t)-IsoP induced a vasoconstriction in a concentration-dependent manner with a pD(2) value of 5.80 +/- 0.05, whereas 2,3-dinor-15-F(2t)-IsoP and 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP had no effect. The parent compound 15-F(2t)-IsoP was more potent (pD(2) value: 6.46 +/- 0.1). Endothelium removal had no influence on the contraction to 15-keto-15-F(2t)-IsoP. GR32191 (a TP-receptor antagonist) concentration-dependently inhibited the contraction induced by 15-keto-15-F(2t)-IsoP, with a significant decrease in the E(max) values for GR32191 10(-7) M. Pretreatment with 2,3-dinor-15-F(2t)-IsoP and 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP induced no alteration of 15-F(2t)-IsoP concentration-response curves. In contrast, 15-keto-15-F(2t)-IsoP pretreatment competitively inhibited the response to 15-F(2t)-IsoP. When concentration ratios of EC(50) values were used, a Schild regression of this data was linear with a slope of 0.974 and a pA(2) value of 6.13. 15-keto-15-F(2t)-IsoP at high concentrations caused a weak concentration-dependent relaxation of rat aorta rings contracted with U46619 (3.10(-8) M) that was not modified in the absence of endothelium. In contrast, 2,3-dinor-15-F(2t)-IsoP and 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP induced no vasodilation. In conclusion, among the F(2)-isoprostane metabolites, 2,3-dinor-15-F(2t)-IsoP and 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP did not cause vasorelaxation or vasoconstriction on the rat thoracic aorta. In contrast, 15-keto-15-F(2t)-IsoP mediates contraction through activation of TP-receptors, probably as a partial agonist, and induces a weak endothelium-independent relaxation at high concentrations.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Aorta, Thoracic; Biphenyl Compounds; Dinoprost; Endothelium, Vascular; F2-Isoprostanes; Heptanoic Acids; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Potassium Chloride; Prostaglandin Antagonists; Prostaglandins F, Synthetic; Rats; Rats, Wistar; Receptors, Prostaglandin; Receptors, Thromboxane; Vasoconstriction; Vasoconstrictor Agents; Vasodilation

Prostaglandins (PG) E1, E2 and F2alpha induce bone resorption in isolated neonatal parietal bone cultures, and an associated increase in interleukin-6 (IL-6) production. Indomethacin had little effect on the response to PGE2, or the relatively non-selective EP receptor agonists 11-deoxy PGE1 and misoprostol, but blocked the effects of PGF2alpha and the F receptor agonist fluprostenol, indicating an indirect action via release of other prostaglandins. It is more likely that there is positive autoregulation of prostaglandins production in this preparation mediated via stimulation of F receptors. The effects of selective EP receptor agonists sulprostone (EP1,3) and 17-phenyl trinor PGE2(EP1), indicated the involvement of EP2 and/or EP4 receptors, which signal via cAMP. The relatively weak increase in IL-6 production by misoprostol (with respect to resorption) suggests that these responses are controlled by different combination of EP2 and EP4 receptors. The PKA activator, forskolin, induced small increases in bone resorption at lower concentrations (50-500 ng/ml) but a reversal of this effect, and inhibition of resorption induced by other stimuli (PTH, PGE2), at higher concentrations (0.5-5 microg/ml). IL-6 production was markedly increased only at the higher concentrations. The inhibitory effect of forskolin may be a calcitonin-mimetic effect. PMA induced both resorption and IL-6 production which were both blocked by indomethacin, indicating a role for PKC in the control of prostaglandin production.

Topics: Alprostadil; Animals; Animals, Newborn; Bone Resorption; Colforsin; Culture Techniques; Cyclic AMP-Dependent Protein Kinases; Dinoprost; Dinoprostone; Dose-Response Relationship, Drug; Indomethacin; Mice; Misoprostol; Prostaglandins; Prostaglandins F, Synthetic; Skull

Prostaglandin F2alpha (PGF2alpha) is a bioactive lipid mediator which has been suggested to be involved in the pathogenesis of periodontal disease. However, the roles of PGF2alpha in periodontal lesions are poorly understood. In the present study, we investigated the effect of PGF2alpha on interleukin (IL)-6 production in human gingival fibroblasts (HGF). PGF2alpha stimulated IL-6 production in a time- and concentration-dependent fashion. IL-1beta and tumor necrosis factor alpha (TNFalpha), proinflammatory cytokines, induced IL-6 production in a time-dependent manner, and PGF2alpha synergistically enhanced IL-6 production induced by IL-1beta and TNFalpha. IL-6 mRNA was expressed in PGF2alpha-stimulated HGF, and PGF2alpha increased IL-6 mRNA levels induced by IL-1beta and TNFalpha. Fluprostenol, a selective FP receptor agonist, could mimic PGF2alpha-induced IL-6 production. Since FP receptors are coupled to elevation of intracellular calcium and activation of protein kinase C (PKC), the mechanism of IL-6 production by PGF2alpha was investigated using TMB-8, an inhibitor of Ca2+ mobilization from intracellular stores, and calphostin C, an inhibitor of PKC. TMB-8 significantly suppressed PGF2alpha-induced IL-6 production, whereas calphostin C showed a stimulatory effect on PGF2alpha-induced IL-6 production. From these data, we suggest that PGF2alpha upregulates IL-6 production through FP receptors in HGF, that PGF2alpha synergistically enhances IL-6 production in IL-1beta- and TNFalpha-stimulated HGF, and that PGF2alpha-induced IL-6 production may be dependent on intracellular Ca2+ mobilization and be downregulated by PKC activation. PGF2alpha may be involved in the pathogenesis of periodontal disease by enhancing IL-6 levels in periodontal lesions.

Topics: Calcium; Calcium Channel Blockers; Cells, Cultured; Dinoprost; Dose-Response Relationship, Drug; Down-Regulation; Drug Synergism; Enzyme Activation; Enzyme Inhibitors; Fibroblasts; Gallic Acid; Gene Expression Regulation; Gingiva; Humans; Inflammation Mediators; Interleukin-1; Interleukin-6; Naphthalenes; Periodontal Diseases; Prostaglandins F, Synthetic; Protein Kinase C; Receptors, Prostaglandin; RNA, Messenger; Time Factors; Tumor Necrosis Factor-alpha; Up-Regulation

In human pregnancy, cortisol and PGs are involved in the onset of labor and play an important role in the mechanisms leading to parturition. Recent studies have shown that at term, cortisol increases PG synthesis and decreases PG metabolism in chorion trophoblast (CT) cells. In CT, 11 beta-hydroxysteroid oxidase type 1 (11 beta-HSD1) converts biologically inactive cortisone to cortisol to regulate cortisol availability. In the present study, we have investigated whether 11 beta-HSD1 activity could be influenced by PGs. We have shown that in CT, PGF2alpha rapidly increased 11 beta-HSD1 reductase activity in a dose-dependent manner via the PGF2alpha receptor, localized in the fetal membranes. PGF2alpha stimulated 11 beta-HSD1 activity through increased intracellular calcium mobilization, activation of PKC, and the phosphorylation of the 11 beta-HSD enzyme. We propose that within CT there is a novel feed forward loop by which PGF2alpha acts to promote cortisol production from cortisone through increases in 11beta-HSD1, and this in turn leads to further net PG output for the onset of labor and birth.

Topics: 11-beta-Hydroxysteroid Dehydrogenases; Adult; Calcium; Cells, Cultured; Dinoprost; Feedback; Female; Fetus; Fluorescent Dyes; Fura-2; Humans; Hydrocortisone; Hydroxysteroid Dehydrogenases; Immunohistochemistry; Labor, Obstetric; Luteolytic Agents; Membranes; Precipitin Tests; Pregnancy; Prostaglandins F, Synthetic; Receptors, Prostaglandin; Stimulation, Chemical; Trophoblasts

Replacement of the carboxylic acid group of PGF(2alpha) with the non-acidic substituents hydroxyl (-OH) or methoxy (-OCH(3)) resulted in an unexpected activity profile. Although PGF(2alpha) 1-OH and PGF(2alpha) 1-OCH(3) exhibited potent contractile effects similar to 17-phenyl PGF(2alpha) in the cat lung parenchymal preparation, they were approximately 1000 times less potent than 17-phenyl PGF(2alpha) in stimulating recombinant feline and human FP receptors. In human dermal fibroblasts and Swiss 3T3 cells PGF(2alpha) 1-OH and PGF(2alpha) 1-OCH(3) produced no Ca(2+) signal until a 1 microM concentration was exceeded. Pretreatment of Swiss 3T3 cells with either 1 microM PGF(2alpha) 1-OH or PGF(2alpha) 1-OCH(3) did not attenuate Ca(2+) signal responses produced by PGF(2alpha) or fluprostenol. In the rat uterus, PGF(2alpha) 1-OH was about two orders of magnitude less potent than 17-phenyl PGF(2alpha) whereas PGF(2alpha) 1-OCH(3) produced only a minimal effect. Radioligand binding studies on cat lung parenchymal plasma membrane preparations suggested that the cat lung parenchyma does not contain a homogeneous population of receptors that equally respond to PGF(2alpha)1-OH, PGF(2alpha)1-OCH(3), and classical FP receptor agonists. Studies on smooth muscle preparations and cells containing DP, EP(1), EP(2), EP(3), EP(4), IP, and TP receptors indicated that the activity of PGF(2alpha) 1-OH and PGF(2alpha) 1-OCH(3) could not be ascribed to interaction with these receptors. The potent effects of PGF(2alpha) 1-OH and PGF(2alpha) 1-OCH(3) on the cat lung parenchyma are difficult to describe in terms of interaction with the FP or any other known prostanoid receptor.

Topics: 3T3 Cells; Animals; Binding, Competitive; Calcium; Cats; Cell Line; COS Cells; Dinoprost; DNA, Recombinant; Dose-Response Relationship, Drug; Female; Guinea Pigs; Humans; In Vitro Techniques; Mice; Muscle Contraction; Muscle, Smooth; Prostaglandin D2; Prostaglandins F, Synthetic; Rabbits; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Epoprostenol; Receptors, Prostaglandin; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP1 Subtype; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP3 Subtype; Receptors, Prostaglandin E, EP4 Subtype; Receptors, Thromboxane; Structure-Activity Relationship

The aim of this study was to pharmacologically characterize the antagonist properties of a novel prostaglandin F2alpha (PGF2alpha) analogue (11-deoxy-16-fluoro PGF2alpha; AL-3138) using a variety of second-messenger assays of prostaglandin receptor subtypes. A detailed comparison was made between AL-3138 and some purported FP receptor antagonists such as PGF2alpha dimethylamine, PGF2alpha dimethylamide, glibenclamide and phloretin using the FP receptor-mediated phosphoinositide turnover assay in A7r5 rat thoracic aorta smooth muscle cells and mouse Swiss 3T3 fibroblasts. The potency and efficacy of AL-3138 as an FP receptor agonist were: EC50 = 72.2 +/- 17.9 nM (Emax = 37%) (n = 3) in A7r5 cells and EC50 = 20.5 +/- 2.8 nM (Emax = 33%) (n = 5) in 3T3 cells. Being a partial agonist, the antagonist potency of AL-3138 against fluprostenol in A7r5 cells was determined to be: Ki = 296 +/- 17 nM (n = 3) and Kb = 182 +/- 44 nM (n = 5) (-log Kb = 6.79 +/- 0.1). AL-3138 exhibited very minimal or no antagonistic effects at EP2, EP4, DP and TP prostaglandin receptors. Both PGF2alpha dimethylamide and PGF2alpha dimethylamine were inactive as FP receptor antagonists, whereas phloretin and glibenclamide were very weak and had -log Kb values of 5.28 +/- 0.09 (n = 3) and 3.58 +/- 0.32 (n = 3), respectively. However, phloretin antagonized functional responses of EP2 and DP prostanoid receptors, and also the V1-vasopressin receptor. AL-3138 competed for [3H]PGF2alpha binding to FP receptors with a relatively high affinity (IC50high = 312 +/- 95 nM) matching its functional antagonist potency. In conclusion, AL-3138 is a more potent and selective FP receptor antagonist than glibenclamide, phloretin, PGF2alpha dimethylamide and PGF2alpha dimethylamine and is therefore a unique and novel pharmacological tool to help characterize FP receptor-mediated functions.

Topics: 3T3 Cells; Animals; Binding, Competitive; Cattle; Cell Line; Cell Line, Transformed; CHO Cells; Corpus Luteum; Cricetinae; Cyclic AMP; Dinoprost; Dose-Response Relationship, Drug; Female; Glyburide; Humans; Inositol Phosphates; Membranes; Mice; Phloretin; Prostaglandin Antagonists; Prostaglandins F, Synthetic; Radioligand Assay; Receptors, Prostaglandin

We examined the effect of PGs, particularly PGF2alpha, on basic fibroblast growth factor-2 (FGF-2) messenger RNA (mRNA) and protein in the rat osteoblastic cell line Py1a and in fetal rat calvariae. Py1a cells expressed multiple FGF-2 mRNA transcripts. PGF2alpha dose-dependently increased the 6-kb transcript at 6 h. The selective PGF2alpha agonist, fluprostenol (Flup), was more potent than PGF2alpha. Phorbol myristate acetate (10(-6) M) also increased a 6-kb mRNA at 6 h. By immunofluorescence microscopy, Flup increased perinuclear staining for FGF-2 protein at 6 h and nuclear labeling at 24 h. Immunogold labeling of calvariae revealed that treatment with Flup for 3 h caused a transition of FGF expression from matrix to cells and an increase in cytoplasmic labeling for FGF-2 protein in periosteal cells and in osteoblasts. After treatment with Flup for 24 h, nuclear labeling was marked in periosteal cells and in osteoblasts, and a further increase in cytoplasmic labeling for FGF-2 was noted in osteocytes, periosteal cells, and osteoblasts. We conclude that PGs can increase FGF-2 mRNA and protein in bone cells. Because the effect of Flup was mimicked by phorbol myristate acetate, we hypothesize that PGs' regulation of FGF-2 is mediated by a PGF2alpha-selective receptor acting through protein kinase C. Hence, effects of PGs on bone remodeling may be mediated, in part, by endogenous FGF-2.

Topics: Animals; Bone and Bones; Cells, Cultured; Dinoprost; Fibroblast Growth Factor 2; Gene Expression Regulation; Luteolytic Agents; Osteoblasts; Prostaglandins; Prostaglandins F, Synthetic; Rats; Rats, Sprague-Dawley; RNA, Messenger

AL-5848 (5Z,13E)-(9 S,11R,15S)-9,11,15-trihydroxy-5,13-prostadienoic acid) is the carboxylic acid of travoprost (AL-6221), a single (+)-isomer of (+/-)-fluprostenol, an FP-class prostaglandin agonist which lowers intraocular pressure. We have prepared a radioligand from this selective prostaglandin and demonstrated its utility for studying the pharmacology and autoradiographic location of the FP-receptor. Specific [3H]AL-5848 binding (84% of total) was linearly related to bovine corpus luteum tissue concentration and reached equilibrium within 275 min at 23 degrees C. Scatchard analysis of saturation isotherms indicated interaction of [3H]AL-5848 with a single class of high-affinity (dissociation constant, Kd, = 33.8+/-2.9 nM, n = 4) and saturable (Bmax = 37.3+/-3.0 pmol (g wet weight tissue)(-1)) FP receptor-binding sites in bovine corpus luteum. Specific [3H]AL-5848 binding was potently inhibited by the FP-receptor ligands 16-phenoxyPGF2alpha (inhibition constant Ki = 17.3 nM); cloprostenol (Ki = 56.8 nM); 17-phenyl PGF2alpha (Ki = 87.0 nM); AL-5848 (Ki = 52.1 nM); PGF2alpha (Ki = 195 nM); PHXA85 (Ki = 223 nM); (n = 3-11) but very weakly by PGD2, ZK118182, BW245C, PGE2, PGI2 and U-46619. The pharmacology of specific [3H]AL-5848 binding correlated well with the pharmacology of [3H]PGF2alpha binding in the bovine corpus luteum preparation (r = 0.98, n = 14, P<0.0001) and also with functional responses in Swiss 3T3 and rat vascular smooth muscle cells (A7r5) (r = 0.96) expressing FP receptors. Autoradiographic studies revealed high levels of specific FP-receptor binding with [3H]AL-5848 on granulosa cells in the bovine corpus luteum sections, and on longitudinal ciliary muscle, the ciliary process, the iris sphincter and the retina in eye sections from man. These studies show [3H]AL-5848 to be a high-affinity agonist radioligand capable of selectively labelling the FP prostaglandin receptor.

Topics: 3T3 Cells; Adult; Aged; Animals; Autoradiography; Binding Sites; Cattle; Dinoprost; Dose-Response Relationship, Drug; Humans; Mice; Middle Aged; Prostaglandins F, Synthetic; Rats; Receptors, Prostaglandin; Stereoisomerism

This study provided a pharmacological evaluation of prostaglandin binding to bovine luteal plasma membrane. It was found that [3H]PGF2 alpha' [3H]PGE2' [3H]PGE1 and [3H]PGD2 all bound with high affinity to luteal plasma membrane but had different specificities. Binding of [3H]PGF2 alpha and [3H]PGD2 was inhibited by non-radioactive PGF2 alpha (IC50 values of 21 and 9 nmol l-1, respectively), PGD2 (35 and 21 nmol l-1), and PGE2 (223 and 81 nmol l-1), but not by PGE1 (> 10,000 and 5616 nmol l-1). In contrast, [3H]PGE1 was inhibited by non-radioactive PGE1 (14 nmol l-1) and PGE2 (7 nmol l-1), but minimally by PGD2 (2316 nmol l-1) and PGF2 alpha (595 nmol l-1). Binding of [3H]PGE2 was inhibited by all four prostaglandins, but slopes of the dissociation curves indicated two binding sites. Binding of [3H]PGE1 was inhibited, resulting in low IC50 values, by pharmacological agonists that are specific for EP3 receptor and possibly EP2 receptor. High affinity binding of [3H]PGF2 alpha required a C15 hydroxyl group and a C1 carboxylic acid that are present on all physiological prostaglandins. Specificity of binding for the FP receptor depended on the C9 hydroxyl group and the C5/C6 double bond. Alteration of the C11 position had little effect on affinity for the FP receptor. In conclusion, there is a luteal EP receptor with high affinity for PGE1' PGE2' agonists of EP3 receptors, and some agonists of EP2 receptors. The luteal FP receptor binds PGF2 alpha' PGD2 (high affinity), and PGE2 (moderate affinity) but not PGE1 due to affinity determination by the C9 and C5/C6 moieties, but not the C11 moiety.

Topics: Alprostadil; Animals; Binding, Competitive; Cattle; Cell Membrane; Corpus Luteum; Dibenz(b,f)(1,4)oxazepine-10(11H)-carboxylic acid, 8-chloro-, 2-acetylhydrazide; Dinoprost; Dinoprostone; Female; Logistic Models; Luteolytic Agents; Male; Misoprostol; Prostaglandin Antagonists; Prostaglandin D2; Prostaglandins; Prostaglandins F, Synthetic; Protein Binding; Radioligand Assay; Receptors, Prostaglandin; Receptors, Prostaglandin E; Sensitivity and Specificity

Previous studies suggested that FP receptors do not mediate the relaxation of the ciliary muscle and reduction of intraocular pressure in cats by prostaglandin (PG) F2alpha. The present study was undertaken to determine whether the reduction of intraocular pressure in cats induced by PGF2alpha is mediated by FP or other prostaglandin receptors.. One eye of each cat was treated topically with prostaglandin F2alpha, fluprostenol (FP receptor agonist), or 17-phenyl trinor PGE2 (EP1 receptor agonist) in a dose range of 12.5 to 50 microg. The effects of SC19220 and SC51089 (EP1 receptor antagonists), BWA868c, and SQ29548 (DP and TP receptor antagonists, respectively) on the intraocular response to PGF2alpha were also examined. At intervals up to 6 hours after treatment, intraocular pressure was measured with a pneumotonometer, and pupil diameters were measured with a millimeter ruler.. In the dose ranges used, PGF2alpha and 17-phenyl trinor PGE2 decreased intraocular pressure and pupil diameter. The greatest reduction of intraocular pressure by 50.0 microg PGF2alpha was 5.0+/-1.4 mm Hg, whereas that by 50 microg 17-phenyl trinor PGE2 was 6.2+/-1.5 mm Hg. The isopropyl ester of PGF 2alpha at a dose of 1.25 microg reduced intraocular pressure by 3.75+/-0.25 mm Hg at 2 hours. At doses up to 100 microg, fluprostenol did not decrease intraocular pressure but did reduce pupil diameter. SC19220, a weak but selective EP1 receptor antagonist, inhibited the intraocular pressure response to both PGF2alpha and 17-phenyl trinor PGE2. The more potent EP1 receptor antagonist SC51089 had a greater inhibitory effect than SC19220 on the intraocular pressure response to PGF2alpha. Both of these antagonists had a small but non-dose dependent and statistically insignificant effect on the pupil response to PGF2alpha. These observations suggest that in cats, intraocular pressure and pupil responses to PGF2alpha, are mediated by EP1 and FP receptors, respectively. However, SC19220 significantly and dose-dependently inhibited the pupil response to 17-phenyl trinor PGE2alpha suggesting that EP1 receptors mediate pupil response to this agonist. DP and TP receptor antagonists at doses 5- to 20-fold greater than the IC50 values had no effect on the ocular hypotensive response to PGF2alpha. The concurrent administration of 12.5 microg of each of PGF2alpha and 17-phenyl trinor PGE2 did not produce an additive effect on intraocular pressure, indicating that in cats PGF2alpha and 17-phenyl trinor PGE2 act on the same receptor type.. These results suggest that a significant proportion of the ocular hypotensive action of PGF2alpha in cats is mediated by EP1 but not by FP receptor. Evidence was also provided to show that 17-phenyl trinor PGE2 is an ocular hypotensive agent in cats.

Topics: Animals; Cats; Dinoprost; Dose-Response Relationship, Drug; Intraocular Pressure; Latanoprost; Prostaglandin Antagonists; Prostaglandins F, Synthetic; Pupil; Random Allocation; Receptors, Prostaglandin; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP1 Subtype; Tonometry, Ocular

Prostaglandin F2 alpha (PGF2 alpha) has regulatory (mainly luteolytic) effects in the ovary but the mechanism of action is not completely understood. Reverse transcriptase-polymerase chain reaction (RT-PCR) techniques were used to demonstrate the presence of mRNA encoding the PGF2 alpha receptor (FP receptor) in human granulosa-lutein cells. Specific primers for the amplification of cDNA were designed and yielded a single product of 696 bp corresponding to the FP receptor. The identity of this product was verified by sequencing. Fluprostenol, a selective FP receptor agonist, activated phospholipase C (PLC) and increased intracellular free calcium concentration, confirming the functional activation of the receptor. We have demonstrated by Western blotting that granulosa cells express PLC-beta and PLC-gamma isoforms. The cells responded to pervanadate with increased PLC activity and increased tyrosine phosphorylation, demonstrating a functional PLC-gamma tyrosine kinase pathway. However, fluprostenol did not provoke any detectable tyrosine phosphorylation. Moreover, the effect of fluprostenol was inhibited through protein kinase C stimulation by phorbol 12, 13-dibutyrate, and was not affected when cells were treated with phenylarsine oxide, which blocks tyrosine phosphorylation. These results suggest that the FP receptor activates PLC-beta rather than PLC-gamma isoforms. Fluprostenol-induced activation was pertussis toxin resistant. Granulosa cells express G proteins of the Gq family (resistant to pertussis toxin) and mRNA for both G alpha q and G alpha 1 l has been identified by RT-PCR. In conclusion, human granulosa cells have a functional FP receptor the effects of which are mediated through PLC-beta activation probably via Gq/1 l.

Topics: Calcium; Cells, Cultured; Dinoprost; Enzyme Activation; Female; Granulosa Cells; GTP-Binding Proteins; Humans; Isoenzymes; Luteolytic Agents; Polymerase Chain Reaction; Prostaglandins F, Synthetic; Receptors, Prostaglandin; RNA, Messenger; Type C Phospholipases

Treatment of 3T3-L1 preadipocytes with arachidonic acid resulted in a dose-dependent inhibition of adipocyte differentiation. The cells failed to accumulate fat droplets and did not express stearoyl-CoA desaturase 1 mRNA, a marker for late-stage differentiation. The inhibition of differentiation was reversed by the addition of cyclooxygenase inhibitors ibuprofen or indomethacin. Inhibitors of the lipoxygenase and cytochrome P-450 epoxygenase pathways were unable to reverse the effect of arachidonic acid. Dexamethasone, one of the adipogenic agents normally used to induce differentiation, could be replaced with cyclooxygenase inhibitors in the differentiation cocktail. This implicated dexamethasone as a modulator of prostaglandin synthesis in culture. Prostaglandins F2 alpha (ED50 = 0.4 nM), E2, and D2 prevented differentiation, each with a specific, dose-dependent affinity. Prostaglandin F2 alpha was the most potent inhibitor of differentiation, suggesting that a prostanoid FP2 receptor (FP receptor) mediates the prostaglandin action. Fluprostenol (ED50 = 0.3 nM), a selective FP receptor agonist, prevented differentiation, confirming the involvement of an FP receptor in the inhibition of 3T3-L1 preadipocyte differentiation. Stimulation of the FP receptor for 1 h during the first day of differentiation was sufficient to cause substantial inhibition. Endogenous PGF2 alpha production was lower in differentiating cells compared to unstimulated preadipocytes. These data suggest that PGF2 alpha production by preadipocytes plays a role in maintaining the undifferentiated state.

Topics: 3T3 Cells; Adipocytes; Animals; Arachidonic Acid; Cell Differentiation; Dexamethasone; Dinoprost; Dinoprostone; Mice; Prostaglandin D2; Prostaglandins; Prostaglandins F, Synthetic; Receptors, Prostaglandin; Stem Cells; Stimulation, Chemical

We have shown previously that treatment of 3T3-L1 preadipocytes with prostaglandin F2alpha (PGF2alpha) and fluprostenol, a prostanoid FP2 receptor (FP receptor) agonist, inhibited adipocyte differentiation. In this study, we demonstrate that the inhibition by PGF2alpha is controlled by concentrations of PGF2alpha rather than regulation of FP receptor levels or binding. Membranes prepared from either 3T3-L1 preadipocytes or adipocytes exhibited specific binding for PGF2alpha, suggesting that FP receptors are present throughout differentiation. Endogenous PGF2alpha production in 3T3-L1s was lower in differentiating cells compared with uninduced preadipocytes, providing further evidence that regulation occurs at the level of ligand concentration. Stimulation of the FP receptor causes a transient intracellular calcium increase, an activation of a calcium/calmodulin-dependent protein kinase (CaMK), and an increase in DNA synthesis, associated with the inhibition of differentiation. Calcium mobilizing agents, A23187 and thapsigargin, mimic the FP receptor-induced inhibition of differentiation, suggesting a role for calcium. KN-62, a CaMK inhibitor, reversed the inhibition of differentiation when added to differentiating cells with fluprostenol, suggesting a critical role for a CaMK in the inhibition. The activation of CaMK was responsible for an increase in DNA content and thymidine incorporation. The increase in DNA synthesis occurs without a concomitant increase in cell proliferation. Early differentiation markers remain intact with PGF2alpha treatment, defining the interference with normal postconfluent mitosis as the time period of differentiation that is affected by PGF2alpha. These results implicate the modulation of PGF2alpha levels in the inhibition of 3T3-L1 adipocyte differentiation through an FP receptor-mediated increase in intracellular calcium and associated increase in DNA synthesis.

Topics: Adipocytes; Animals; Biomarkers; Calcium; Calcium-Calmodulin-Dependent Protein Kinases; Cell Differentiation; Dinoprost; DNA; Intracellular Membranes; Mice; Prostaglandins; Prostaglandins F, Synthetic; Protein Kinase C; Receptors, Cell Surface; Stem Cells

The objective of this study was to investigate the mechanism of action of PGF2 alpha in cultured human myometrial cells. We measured the effects of PGF2 alpha and fluprostenol, a selective PGF2 alpha receptor (FP receptor) agonist, on phospholipase C(PLC) activation, on changes in the intracellular free calcium concentration ([Ca2+]i), and on protein tyrosine phosphorylation. PGF2 alpha and fluprostenol activated PLC (determined by measuring the formation of inositol phosphates) and increased [Ca2+]i in a concentration-dependent manner. The apparent affinity of the FP receptor for fluprostenol was higher than that for PGF2 alpha when measuring PLC activation, but the receptor displayed similar affinities for both agonists when measuring increases in [Ca2+]i. These effects were not altered by treating the cells with pertussis toxin (PT), suggesting that the FP receptor is linked to PLC activation by a G protein of the Gq family. By contrast, the effect of oxytocin on PLC activation involved both PT-resistant and PT-sensitive pathways. Human myometrial cells responded to pervanadate and epidermal growth factor with increased PLC activity and increased tyrosine phosphorylation, demonstrating a functional PLC-gamma tyrosine kinase pathway. However, neither fluprostenol nor oxytocin stimulated tyrosine phosphorylation, but the effects of both agonists were inhibited after protein kinase C stimulation. These data suggest that fluprostenol and oxytocin activate PLC-beta rather than PLC-gamma isoforms. The effect of fluprostenol is Ca2+ dependent, but is unlikely to involve a direct effect of Ca2+ on PLC activity.

Topics: Biological Transport; Calcium; Cells, Cultured; Dinoprost; Enzyme Activation; Female; Humans; Inositol Phosphates; Intracellular Membranes; Myometrium; Osmolar Concentration; Pertussis Toxin; Phosphorylation; Prostaglandins F, Synthetic; Type C Phospholipases; Tyrosine; Virulence Factors, Bordetella

Several prostaglandins [prostaglandin (PG) A2, -B2, -D2, -E2, -F2 alpha, and -I2 and carbaprostacyclin] and the thromboxane analogue U-46619 were analyzed for the ability to induce hypertrophy of rat neonatal cardiac ventricular myocytes. Myocyte hypertrophy was induced specifically by PGF2 alpha. Myocytes exposed to this prostanoid in culture increased in size and protein content. The contractile fibrils within the cells became organized into parallel arrays, and the cells tended to cluster and beat spontaneously. PGF2 alpha also induced the expression of c-fos, atrial natriuretic factor (ANF), and alpha-skeletal actin in these cells. The effects of PGF2 alpha were compared with several known cardiac myocyte hypertrophy factors (phenylephrine, endothelin-1, leukemia inhibitory factor, cardiotrophin-1, and angiotensin II). PGF2 alpha was found to be intermediate in potency among the factors but induced a level of ANF production that was approximately 10-fold higher than any of the other effectors. Responsiveness to PGF2 alpha was not limited to neonatal cardiocytes. Ventricular myocytes isolated from adult rats also responded specifically to PGF2 alpha with a morphological change similar to that observed with phenylephrine and by producing ANF. In rats, chronic administration of fluprostenol, a potent agonist analogue of PGF2 alpha, resulted in a dose-dependent increase in heart weight- and ventricular weight-to-body weight ratios. The amount of PGF2 alpha extractable from the hearts of rats with cardiac hypertrophy induced by myocardial infarction was also found to be greater than that in sham-operated control rats. These results indicate that PGF2 alpha may play an important role in inducing cardiac hypertrophy.

Topics: Aging; Animals; Animals, Newborn; Atrial Natriuretic Factor; Cardiomegaly; Cells, Cultured; Dinoprost; Heart; Male; Myocardial Infarction; Myocardium; Phenylephrine; Prostaglandins; Prostaglandins F, Synthetic; Rats; Rats, Sprague-Dawley; RNA, Messenger; Time Factors

1. Prostaglandin F2 alpha (PGF2 alpha) and its synthetic analogue, fluprostenol, potently relaxed the precontracted isolated jugular vein of the rabbit (RJuV). The vasorelaxant activity of PGF2 alpha and fluprostenol was dependent upon an intact vascular endothelium. Although removal of the vascular endothelium abolished activity associated with PGF2 alpha-like agonists, it did not significantly alter the relaxant effects of prostaglandin E2 (PGE2). 2. The nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), at 100 microM significantly inhibited the endothelium-dependent relaxations induced by PGF2 alpha. Lower doses (1 microM, 10 microM) of L-NAME had little or no effect. The relaxant effects of PGE2 were not affected by L-NAME (1-100 microM). D-NAME at 100 microM was without effect on the vasorelaxant responses to either PGF2 alpha or PGE2. 3. The potassium (K)-channel blockers tetraethylammonium (TEA, 1 mM), barium (1 mM) and quinine (100 microM), each tested in the presence of the inactive enantiomer D-NAME (100 microM) did not significantly affect the response to PGF2 alpha. Unexpectedly, both TEA and barium significantly and partially reversed the inhibitory effects of 100 microM L-NAME, whereas quinine had no effect. In similar studies, none of the three potassium channel blockers had any effect on relaxations elicited by PGE2 when given with D-NAME or L-NAME. 4. These results indicate that the PGF2 alpha-sensitive prostanoid receptors found in the vascular endothelium of the rabbit jugular vein are of the FP-receptor subtype. Nitric oxide (NO) appears to be the predominant messenger involved in PGF2 alpha-induced relaxation of the rabbit jugular vein. Potassium channels may have a minor role in mediating the vasorelaxation response to PGF2 alpha. When both NO synthesis and K-channels are simultaneously blocked, inhibition of PGF2 alpha-induced vasorelaxation by L-NAME is opposed by K-channel blockers. This diminution of the inhibitory effect of L-NAME by TEA and barium suggests that K-channels may possibly serve a compensatory role via the NO pathway.

Topics: Animals; Dinoprost; Endothelium, Vascular; Enzyme Inhibitors; Female; Jugular Veins; Male; Nitric Oxide Synthase; Potassium Channel Blockers; Prostaglandins F, Synthetic; Rabbits; Receptors, Prostaglandin; Vasodilation

A cDNA clone coding for a functional human prostanoid FP receptor has been isolated from a uterus cDNA library. The human FP receptor consists of 359 amino acid residues with a predicted molecular mass of 40,060, and has the seven putative transmembrane domains characteristic of G-protein-coupled receptors. Challenge of Xenopus oocytes expressing the FP receptor with 10 nM of either prostaglandin (PG) F2 alpha or the selective FP-receptor agonist fluprostenol resulted in an elevation in intracellular Ca2+. Radioreceptor binding studies using membranes prepared from mammalian COS cells transfected with the FP receptor cDNA showed that the rank order of potency for prostaglandins and prostaglandin analogs in competition for [3H]PGF2 alpha specific binding sites was as predicted for the FP receptor, with PGF2 alpha approximately fluprostenol > PGD2 > PGE2 > U46619 > iloprost. In summary, we have cloned the human prostanoid FP receptor which is functionally coupled to the Ca2+ signalling pathway.

Topics: Amino Acid Sequence; Animals; Base Sequence; Calcium; Cell Line; Cloning, Molecular; Dinoprost; DNA, Complementary; Female; Gene Expression; Humans; Kinetics; Mice; Molecular Sequence Data; Molecular Weight; Oligonucleotides, Antisense; Oocytes; Prostaglandins F, Synthetic; Radioligand Assay; Receptors, Prostaglandin; Sequence Homology, Amino Acid; Transfection; Tritium; Uterus; Xenopus laevis

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Calcium; Dinoprost; Dose-Response Relationship, Drug; Fibroblasts; Hydantoins; Mice; Phenylacetates; Platelet-Derived Growth Factor; Prostaglandin Endoperoxides, Synthetic; Prostaglandins; Prostaglandins F, Synthetic; Receptors, Prostaglandin; Sulfonamides

Parturition was induced in 2 groups of mares, less than 300 (n = 49) and 300 to 320 days gestation (n = 31), by the administration of prostaglandin F2 alpha or fluprostenol and oxytocin. Foals were categorized into 4 groups according to their ability to adapt in, and survive, the neonatal period. Group A had no demonstrable coordinating reflexes, were weak from birth, and all died within 90 minutes. Group B had some righting reflexes, but had poor coordination and a weak suck reflex. They showed some improvement for about 2 hours, but all died within 9 hours. Group C foals had a good suck reflex and made attempts to stand. After 24 hours, there was a steady deterioration and death occurred within 48 hours. Group D were initially weak, but showed rapid clinical improvement with good adaptation to the environment and survived for at least 7 days. The overall survival rate for the 80 foals born was only 5%. Most group A foals had gestational ages of less than 300 days, but a few (n = 9) were delivered after 300 days and 2 up to 319 days. The youngest survivor was delivered at 318 days and the 3 other survivors were delivered at 320 days. Aspects of the hazards of prematurely induced parturition were considered to be immaturity and stress of parturition.

Topics: Animals; Animals, Newborn; Behavior, Animal; Dinoprost; Female; Horses; Labor, Induced; Motor Activity; Oxytocin; Pregnancy; Prostaglandins F; Prostaglandins F, Synthetic

The effectiveness of the prostaglandin F analogue fluprostenol in inducing labour in the mare was examined by giving sequential injections over the last 50 days of gestation. The behavioural and endocrine changes elicited by the drug in pregnant and non-pregnant animals and in foals were also studied. Fluprostenol (250 or 500 micrograms intramuscularly) failed to induce labour before 320 days gestation; thereafter its effect was capricious. Twelve mares foaled 1 to 36 h after the last test; eight delivered normal, viable, apparently 'term' foals and four produced stillborn/premature animals. Eight of the deliveries (five term and three pre-term foals) could be ascribed to the action of fluprostenol because they occurred 1 to 6 h after its administration, at a time when spontaneous foaling would have been unlikely. The other four mares foaled between 12 and 36 h after the fluprostenol injection and it is therefore doubtful whether there was a causal relationship between the two events. In the mares which delivered viable foals the pre-partum milk samples were characteristic of full term samples with respect to calcium, sodium and potassium. Those which delivered premature/stillborn foals had low calcium and a high sodium/potassium ratio in the pre-partum milk. Behavioural changes (sweating, increased respiration, defaecation etc), which varied in intensity between tests and individuals, were seen in all three groups of animals following the administration of fluprostenol. These changes were accompanied by rises in plasma cortisol and adrenocorticotrophic hormone concentration during the 2 h sampling period, suggesting a centrally mediated response to the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenocorticotropic Hormone; Animals; Animals, Newborn; Behavior, Animal; Dinoprost; Female; Horses; Hydrocortisone; Labor, Induced; Luteolytic Agents; Pregnancy; Prostaglandins F; Prostaglandins F, Synthetic

Prostaglandin D2 (PGD2) and some naturally occurring and synthetic prostaglandin (PG) analogues were evaluated for irritant/ tussive activity in cats. PGD2, PGF2 alpha and ICI81008 were potent tussive agents when inhaled, producing both an early and late phase of coughing. In addition all three prostaglandins decreased respiratory rate. In contrast PGE2, PGE1 and PGA1 were 100-1000 times less potent than PGF2 alpha as irritants and weakly stimulated respiratory rate. The PGE class of compounds only produced an early phase of coughing. The rank order of early phase tussive activity was ICI81008 greater than PGF2 alpha greater than PGF2 beta much greater than PGE1 = PGE2 = PGA1. This rank order is similar to that characterising the prostanoid 'X' contractant or class II receptor(s).

Topics: Aerosols; Animals; Cats; Cough; Dinoprost; Prostaglandin D2; Prostaglandins D; Prostaglandins F; Prostaglandins F, Synthetic; Receptors, Cell Surface; Receptors, Prostaglandin; Respiration

A neuropathological examination was carried out on the brains of 58 foals. Forty-two were pony foals induced at various periods of gestation from 200 days onwards. Two were pre-viable pony foals delivered by caesarean section and 14 were Thoroughbred foals (one set of twins, two stillborn, five premature, two dysmature, two convulsive and one induced). The only significant pathological change involved intracranial haemorrhage. Subarachnoid haemorrhage occurred in all of 10 pony foals induced before 301 days of gestation and in two pony foals born by caesarean section at 270 and 280 days gestation. Subarachnoid haemorrhage was also present in some pony and Thoroughbred foals born after 301 days gestation; the incidence usually appeared greater in those pony foals which survived for the shortest periods. Haemorrhage also occurred elsewhere in the brains, including the cerebral white matter, the molecular layer of the cerebellum and the medulla, but the intensity could not be related to either length of gestation or duration of survival. No other neuropathological changes were found that could account for the functional state of the animals, whether they were pre-viable, premature, dysmature or convulsive.

Topics: Animals; Animals, Newborn; Brain; Cerebral Hemorrhage; Dinoprost; Female; Fetal Death; Horse Diseases; Horses; Labor, Induced; Luteolytic Agents; Pregnancy; Prostaglandins F; Prostaglandins F, Synthetic

Various regimens of prostaglandins, alone or followed by oxytocin, were given to induce parturition in mares during the pre-viable and premature periods of gestation and in near-term mares. The most successful method of induction was found to be 2 i.m. injections of 500 micrograms fluprostenol (Equimate: I.C.I.) at a 2-h interval followed (if necessary) by 10-20 i.u. oxytocin injected i.v. in 5 i.u. serial increments every 15-20 min. Peak concentrations of the prostaglandin metabolite (PGFM) in response to the inducing agents were shown to be associated with delivery at, but not before, 320 days of gestation. A radiolabelled study of [14C]fluprostenol distribution showed that fluprostenol was present in placenta, amnion, allantoic and amniotic fluid, and in foal plasma and liver.

Topics: Animals; Dinoprost; Extraembryonic Membranes; Female; Horses; Labor, Induced; Labor, Obstetric; Luteolytic Agents; Oxytocin; Placenta; Pregnancy; Pregnancy, Animal; Prostaglandins F; Prostaglandins F, Synthetic; Prostanoic Acids