prostaglandin-d2 and butaprost

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. Since the role of prostanoid receptors in intestinal peristalsis is largely unknown, the peristaltic motor effects of some prostaglandin (DP, EP, IP), thromboxane (TP) and leukotriene (LT) receptor agonists and antagonists were investigated. 2. Propulsive peristalsis in fluid-perfused segments from the guinea-pig small intestine was triggered by a rise of the intraluminal pressure and recorded via the intraluminal pressure changes associated with the peristaltic waves. Alterations of distension sensitivity were deduced from alterations of the peristaltic pressure threshold and modifications of peristaltic performance were reflected by modifications of the amplitude, maximal acceleration and residual baseline pressure of the peristaltic waves. 3. Four categories of peristaltic motor effects became apparent: a decrease in distension sensitivity and peristaltic performance as induced by the EP1/EP3 receptor agonist sulprostone and the TP receptor agonist U-46619 (1-1000 nM); a decrease in distension sensitivity without a major change in peristaltic performance as induced by PGD(2) (3-300 nM) and LTD(4) (10-100 nM); a decrease in peristaltic performance without a major change in distension sensitivity as induced by PGE(1), PGE(2) (1-1000 nM) and the EP1/IP receptor agonist iloprost (1-100 nM); and a decrease in peristaltic performance associated with an increase in distension sensitivity as induced by the EP2 receptor agonist butaprost (1-1000 nM). The DP receptor agonist BW-245 C (1-1000 nM) was without effect. 4. The peristaltic motor action of sulprostone remained unchanged by the EP1 receptor antagonist SC-51089 (1 micro M) and the DP/EP1/EP2 receptor antagonist AH-6809 (30 micro M), whereas that of U-46619 and LTD(4) was prevented by the TP receptor antagonist SQ-29548 (10 micro M) and the cysteinyl-leukotriene(1) (cysLT(1)) receptor antagonist tomelukast (10 micro M), respectively. 5. These observations and their pharmacological analysis indicate that activation of EP2, EP3, IP, TP and cysLT(1) receptors, but not DP receptors, modulate intestinal peristalsis in a receptor-selective manner, whereas activation of EP1 seems to be without influence on propulsive peristalsis. In a wider perspective it appears as if the effect of prostanoid receptor agonists to induce diarrhoea is due to their prosecretory but not peristaltic motor action.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Alprostadil; Animals; Bridged Bicyclo Compounds, Heterocyclic; Dinoprostone; Dose-Response Relationship, Drug; Fatty Acids, Unsaturated; Female; Guinea Pigs; Hydantoins; Hydrazines; Iloprost; In Vitro Techniques; Intestine, Small; Leukotriene Antagonists; Leukotriene D4; Male; Oxazepines; Peristalsis; Prostaglandin D2; Prostaglandins A; Receptors, Leukotriene; Receptors, Prostaglandin; Xanthenes; Xanthones; Yohimbine

Alteration of neutrophil function is associated with their migration from blood into tissue. We evaluated this alteration in both human and rabbit neutrophils, by comparing the inhibitory effects of prostanoids on formylmethionyl-leucyl-phenylalanine (fMLP)-stimulated superoxide generation in human circulating blood neutrophils with those in saliva, and also comparing rabbit circulating blood neutrophils with those exudated into peritoneal cavity. We showed that EP-receptor agonists (PGE1) EP2/EP3 agonist (misoprostol), EP2-receptor agonist (butaprost) and DP-receptor agonist (PGD2) inhibited fMLP-stimulated superoxide production from human blood neutrophils in a concentration-dependent manner. In contrast, these prostanoids produced a significantly smaller maximum inhibition of fMLP-stimulated superoxide production in salivary neutrophils compared to those in blood neutrophils. Similar differences were observed for rabbit blood and peritoneal neutrophils. The inhibitory effect of EP2 agonist (butaprost) on the fMLP-stimulated superoxide generation in human blood neutrophils was significantly higher than that of EP3 agonist (ONO-AP-324). The EP1 antagonist (SC-51322) and EP4 antagonist (AH23848B) employed in this study could not antagonize the inhibitory effect of PGE2. TP agonist (U-46619) failed to show any inhibitory effect in either blood or salivary neutrophils. These results indicated that EP2 and DP receptors are the primary receptors mediating the prostanoids inhibition of fMLP-stimulated superoxide generation from neutrophils. Furthermore, it can be concluded that neutrophils become less responsive to prostanoids in terms of fMLP-stimulated superoxide production in association with their migration from blood to tissue.

Topics: Alprostadil; Animals; Cell Movement; Humans; Misoprostol; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Peritoneal Cavity; Prostaglandin D2; Prostaglandins; Rabbits; Receptors, Prostaglandin; Salivary Glands; Stimulation, Chemical; Superoxide Dismutase; Superoxides

1. Prostanoids induce a wide range of biological actions which are mediated by specific membrane-bound receptors. We have recently shown that the E-type prostaglandins, PGE1 and PGE2, effectively inhibit eosinophil aggregation induced by platelet-activating factor (PAF). In an attempt to determine which prostanoid receptor(s) were involved, we investigated the effects of a range of selective prostanoid agonists and antagonists on eosinophil homotypic aggregation induced by PAF. 2. Both PGE1 and PGE2 (10(-10) to 10(-6) M) induced a concentration-related inhibition of the aggregation response induced by PAF. PGE1 was more effective than PGE2 but PGE2 was slightly more potent than PGE1 (approximate IC50 values for PGE1 and PGE2 of 1.5 x 10(-8) M and 5 x 10(-9) M, respectively). 3. The EP2-selective agonists, 11-deoxy-PGE1, butaprost and AH13205, and the EP2/EP3-selective agonist, misoprostol, also inhibited PAF-induced aggregation. The rank order of potency for EP2-selective agonists was 11-deoxy-PGE1 > misoprostol > butaprost = AH13205. The protein kinase A inhibitor, KT5720 (10(-6) M), reversed the inhibitory effects of 11-deoxy-PGE1 (10(-6) M) and AH13205 (10(-5) M). 4. The EP1/EP3-selective agonist, sulprostone, and the EP1-selective agonist, 17-phenyl-omega-trinor PGE2, had no significant inhibitory activity when tested at concentrations up to 10(-6) M. The EP4-receptor antagonist, AH23848B, had no effect on PAF-induced aggregation and did affect the inhibitory activity of PGE1. 5. The IP-selective agonist, cicaprost (up to 10(-6) M), and the IP/EP1-receptor agonist, iloprost (up to 10(-5) M), had no significant effect on PAF-induced eosinophil aggregation. However, iloprost significantly augmented the inhibitory effects of a maximally inhibitory concentration of PGE2. 6. PGD2 (10(-5) M) had no effect on eosinophil aggregation and the inhibitory activity of PGE1 on PAF-induced eosinophil aggregation was not altered by the DP-selective receptor antagonist, BWA868C. 7. The results presented here suggest that the inhibition of PAF-induced eosinophil aggregation by prostanoids is mediated by the occupation of EP2-receptors. It is important to note that the effects of naturally occurring prostanoids, such as PGE2, on eosinophil aggregation occur at low concentrations highlighting a potential role for EP2 receptors in regulating eosinophil function in vivo.

Topics: Alprostadil; Analysis of Variance; Animals; Anti-Ulcer Agents; Carbazoles; Cell Aggregation; Dinoprostone; Dose-Response Relationship, Drug; Eosinophils; Female; Guinea Pigs; Indoles; Misoprostol; Oxytocics; Platelet Activating Factor; Platelet Aggregation Inhibitors; Prostaglandin D2; Prostaglandins E, Synthetic; Prostanoic Acids; Protein Kinase C; Pyrroles; Receptors, Prostaglandin; Structure-Activity Relationship

The structure-activity relations and signal transduction pathways for the anabolic effects of prostaglandins were examined in cultured fetal rat calvariae. In the presence of cortisol prostaglandins of the E and F series (10(-9) to 10(-5) M) produced a dose-related increase in [3H]thymidine incorporation up to 4-fold at 24 h. Prostaglandin E2 (PGE2) was also effective in the absence of cortisol. Butaprost (10(-6) M), a selective EP-2 receptor agonist, produced partial stimulation. Prostaglandin D2, prostacyclin, sulprostone, an EP-1 and EP-3 receptor agonist, and fluprostenol, an FP receptor agonist, were ineffective. Forskolin (10(-4) M) increased [3H]thymidine incorporation 3-fold, while phorbol myristate acetate (PMA) (10(-6) M) produced a 1.8-fold increase. Isobutylmethylxanthine (IBMX) increased [3H]thymidine incorporation in control cultures, in the absence of cortisol, and increased the response to PGE2 in control and cortisol-treated cultures. [3H]proline incorporation into collagen and noncollagen protein was measured in the continuous presence of prostaglandins and cortisol for 72-96 h (continuous model) or when prostaglandins and cortisol were applied for 24 h, followed by culture for 48 h in control medium (on/off model). The effects on collagen were greater than on noncollagen proteins, so that the percent of collagen synthesis increased. The effects of prostaglandins and forskolin paralleled their mitogenic effects. PMA increased only noncollagen protein. Indomethacin did not diminish the anabolic response, while aphidicolin produced only partial inhibition. We conclude that the anabolic effects of prostaglandins on replication and differentiation of osteoblasts are likely to be mediated by an EP-2 receptor that stimulates adenylate cyclase.

Topics: 1-Methyl-3-isobutylxanthine; Abortifacient Agents, Nonsteroidal; Alprostadil; Animals; Cell Differentiation; Collagen; Dinoprostone; Dose-Response Relationship, Drug; Drug Synergism; Epoprostenol; Hydrocortisone; Isotope Labeling; Organ Culture Techniques; Osteoblasts; Oxytocics; Phosphodiesterase Inhibitors; Prostaglandin D2; Prostaglandins E, Synthetic; Prostaglandins F, Synthetic; Rats; Signal Transduction; Thymidine; Tritium