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Biomedical Research (Tokyo, Japan) Apr 2010Ceramide is generated by the hydrolysis of membrane sphingomyelin by sphingomyelinase and is implicated in multiple signaling pathways, including those regulating...
Ceramide is generated by the hydrolysis of membrane sphingomyelin by sphingomyelinase and is implicated in multiple signaling pathways, including those regulating differentiation, inflammation and immune responses. Excess formation of prostaglandin E(2) (PGE(2)) is thought to increase susceptibility to infection, rheumatoid arthritis and inflammation, including periodontal diseases. We investigated the inhibitory effect of C(2)-ceramide, a short-chain ceramide analog, on the PGE(2)-stimulated accumulation of cAMP in human gingival fibroblasts. In human gingival fibroblasts pre-treated with C(2)-ceramide for 18 h, the PGE(2)-stimulated accumulation of cAMP was reduced, but an inactive C(2)-ceramide analog had no such effect. The accumulation of cAMP induced by EP2 and EP4 receptor agonists (ONO-AE1-259 and ONO-AE1-329, respectively) was inhibited in cells treated with C(2)-ceramide. However, treatment with C(2)-ceramide had no effect on the expression of mRNAs encoding the EP2 and EP4 receptors. Accumulation of cAMP could be induced by cAMP-elevating agents (forskolin, isobutylmethylxanthine and mastparan) but was not reduced by treatment with C(2)-ceramide. These observations suggest that C(2)-ceramide attenuates PGE(2) receptor function and consequently inhibits the accumulation of cAMP in human gingival fibroblasts.
Topics: Arthritis, Rheumatoid; Cell Differentiation; Ceramides; Colforsin; Dinoprostone; Fibroblasts; Gingiva; Humans; Methyl Ethers; Prostaglandins E; RNA, Messenger; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP4 Subtype; Signal Transduction; Sphingomyelins; Sphingosine
PubMed: 20460737
DOI: 10.2220/biomedres.31.97 -
British Journal of Experimental... Dec 1982Whole blood was heated in vitro and incubated with any of the following: epinephrine, norepinephrine, prostaglandin E1, prostaglandin E2 or prostaglandin F2 alpha. The...
Whole blood was heated in vitro and incubated with any of the following: epinephrine, norepinephrine, prostaglandin E1, prostaglandin E2 or prostaglandin F2 alpha. The treatment was assessed by whole-blood filtration and extrusion of a Ca2+ load from Ca2+ loaded red cells. Epinephrine did not affect the parameters measured. Norepinephrine increased cell filtration times and delayed Ca2+ extrusion. Prostaglandin E1 acted in an opposite manner. prostaglandin E2 and F2 alpha both decreased red-cell deformability and Ca2+ extrusion above the effect of heat alone Prostaglandin E2 showed the most pronounced effect. Possible implications of the findings for microcirculation in burned patients are discussed.
Topics: Alprostadil; Calcium; Dinoprostone; Epinephrine; Erythrocytes; Hot Temperature; Humans; Norepinephrine; Prostaglandins; Prostaglandins E; Prostaglandins F; Ultrafiltration
PubMed: 6960925
DOI: No ID Found -
British Journal of Pharmacology Apr 1984Helically cut strips of rabbit aorta, extrapulmonary artery, coeliac artery, and femoral artery were set up in organ baths. Contractions of the strips by noradrenaline... (Comparative Study)
Comparative Study
Helically cut strips of rabbit aorta, extrapulmonary artery, coeliac artery, and femoral artery were set up in organ baths. Contractions of the strips by noradrenaline and angiotensin II were recorded isotonically. The release of prostaglandins 6-keto-PGF1 alpha, E2, F2 alpha, D2 and thromboxane B2 from the strips was measured by means of sensitive and specific radioimmunoassays. All blood vessels released a characteristic pattern of cyclo-oxygenase products. Prostacyclin (PGI2, measured as 6-keto-PGF1 alpha) was the major compound formed, followed by smaller amounts of PGE2 and traces of PGF2 alpha, PGD2 and thromboxane A2 (measured as thromboxane B2). The pulmonary and the femoral artery had comparatively high abilities to synthesize PGE2. Contractions induced by noradrenaline increased prostaglandin release from the pulmonary artery but not from the other blood vessels. Angiotensin II-induced contractions were accompanied by a marked prostaglandin release from the coeliac artery. After angiotensin II, prostaglandin release was also enhanced in the pulmonary artery, but remained essentially unchanged in the aorta and femoral artery. Arachidonic acid markedly increased the levels of all prostaglandin formed. Indomethacin inhibited the formation of all prostaglandins below the detection limits of the respective radioimmunoassays. Indomethacin treatment induced a qualitatively similar shifting of the concentration-response curves of noradrenaline and angiotensin II in some vessels: the concentration-response curves remained unchanged for the aorta, were slightly shifted to the left of the pulmonary artery, were markedly shifted to the left for the coeliac artery, and were shifted to the right for the femoral artery. 7 Exogenous PGI2 strongly and concentration-dependently inhibited contractions induced by the approximate EC50 of noradrenaline in the coeliac artery, but was without effect on the other three preparations. PGE2 had no effect on noradrenaline-induced contractions of the aorta, inhibited those of the pulmonary and the coeliac artery, but markedly potentiated those of the femoral artery. PGF2 alpha significantly enhanced contractions of the femoral artery, but increased contractions of the other preparations were not significant. PGD2 was without effect on any preparation. 8 In conclusion, the contractility of the aorta does not seem to be modulated substantially by prostaglandins. The major prostanoid regulating the tone of the coeliac artery was found to be PGI2. The contractility of the pulmonary and especially the femoral artery is probably not modulated by PGI2 but rather by PGE2. 9 These observations suggest that in certain blood vessels, prostaglandins other than PGI2 are important endogenous modulators of contractility.
Topics: Angiotensin II; Animals; Arteries; Cyclooxygenase Inhibitors; Dinoprostone; Epoprostenol; Female; In Vitro Techniques; Indomethacin; Male; Muscle Contraction; Muscle, Smooth, Vascular; Norepinephrine; Prostaglandins; Prostaglandins E; Rabbits
PubMed: 6426568
DOI: 10.1111/j.1476-5381.1984.tb16127.x -
Postgraduate Medical Journal Nov 1977The role of prostaglandins in inflammation is still disputed. Some workers have attempted to fit prostaglandins into a simple model, i.e. inflammatory leads to chemical...
The role of prostaglandins in inflammation is still disputed. Some workers have attempted to fit prostaglandins into a simple model, i.e. inflammatory leads to chemical mediator leads to vascular response. Recent work has shown that this approach may be misleading. An alternative model is proposed, involving the interaction of two chemical agents, i.e. a vascular permeability-increasing mediator (such as histamine or bradykinin) and a vasodilator (prostaglandin) which potentiates the plasma exudation produced by the permeability-increasing mediator. The results obtained in testing this model support the further proposal that non-steroidal anti-inflammatory compounds suppress inflammatory swelling by inhibiting vasodilatation.
Topics: Animals; Capillary Permeability; Dose-Response Relationship, Drug; Edema; Inflammation; Male; Models, Biological; Prostaglandins; Prostaglandins E; Rabbits; Skin; Vasodilation
PubMed: 593990
DOI: 10.1136/pgmj.53.625.660 -
British Journal of Pharmacology Nov 19791 delta'-trans-Tetrahydrocannabinol (THC) is more active orally in mice than previously thought, as cataleptic responses occur at doses from 0.06 mg/kg upwards, with...
1 delta'-trans-Tetrahydrocannabinol (THC) is more active orally in mice than previously thought, as cataleptic responses occur at doses from 0.06 mg/kg upwards, with peak activity at 2 to 4 h after dosing. These doses and peaks correspond well with the effects in man. 2 Comparison with chlorpromazine in mice shows that chlorpromazine and THC are equipotent as cataleptics during the first 2 h after dosing; thereafter the THC activity increases to a peak when it is 5.67 times as active as chlorpromazine. 3 The cataleptic effect of THC is abolished by aspirin, indomethacine, diffunisal and phenylbutazone which inhibit the biosynthesis of prostaglandins and is restored by exogenous prostaglandin E2 (PGE2) but not PGE1 and PGF2 alpha. This suggests that the effect of THC depends upon the presence of PGE2. 4 In contrast, the cataleptic effect of chlorpromazine is not affected by pretreatment with aspirin. 5 THC is very much less active intraperitoneally than orally; our results suggest this is not due to poor absorption or extraction into fat depots. 6 Cannabidiol has no cataleptic effect.
Topics: Animals; Cannabidiol; Catalepsy; Chlorpromazine; Dronabinol; Drug Interactions; Humans; Male; Mice; Prostaglandin Antagonists; Prostaglandins E; Time Factors
PubMed: 574040
DOI: 10.1111/j.1476-5381.1979.tb08691.x -
The Journal of Biological Chemistry Jul 1986Ram semen was found to contain 20-hydroxyprostaglandin E1 and 20-hydroxyprostaglandin E2. The relative amounts of the two compounds were almost equal, although ram semen...
Ram semen was found to contain 20-hydroxyprostaglandin E1 and 20-hydroxyprostaglandin E2. The relative amounts of the two compounds were almost equal, although ram semen contained at least 10 times more prostaglandin E1 than prostaglandin E2. The accessory genital glands of the ram were analyzed for their capacity to metabolize [14C]arachidonic acid to prostaglandins. Biosynthesis of prostaglandins was only found in microsomes of the mucosa of the ampulla of vas deferens and in microsomes of the vesicular glands. Ram vesicular glands and the ampulla of vas deferens were also found to contain the two 20-hydroxylated E prostaglandins. Microsomes of ram vesicular glands and NADPH metabolized exogenous prostaglandin E2 to 20-hydroxyprostaglandin E2 albeit in low yields. Prostaglandin E2 appeared to be a better substrate than prostaglandin E1. Microsomes of human seminal vesicles and NADPH metabolized exogenous prostaglandin E2 to 19-hydroxyprostaglandin E2. The results show that 19- and 20-hydroxylation of prostaglandins occurs in human and ram seminal vesicles, respectively, and possibly also in the ampulla of vas deferens of the ram. The ram and human enzymes specifically hydroxylated the terminal and the penultimate carbon of prostaglandin E2, respectively.
Topics: Alprostadil; Animals; Arachidonic Acid; Arachidonic Acids; Chromatography, High Pressure Liquid; Dinoprostone; Humans; Male; Microsomes; NADP; Prostaglandins E; Semen; Seminal Vesicles; Sheep; Vas Deferens
PubMed: 3087990
DOI: No ID Found -
British Journal of Clinical Pharmacology Oct 1985Inhaled PGF2 alpha and PGE2 were evaluated for relative tussive activity to non-prostanoid tussive agents. In addition a comparison was sought between the present... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Inhaled PGF2 alpha and PGE2 were evaluated for relative tussive activity to non-prostanoid tussive agents. In addition a comparison was sought between the present observations and those in the cat, the only laboratory animal which consistently coughs to prostanoids. Five healthy volunteers were repeatedly challenged at 90 min intervals with aerosols of PGE2 (100-500 micrograms ml-1) and tussive activity was monitored. In a second separate study again monitoring tussive activity 10 healthy volunteers inhaled aerosols of either PGF2 alpha (0.1-100 micrograms ml-1), PGE2 (0.1-100 micrograms ml-1), acetylcholine (0.1-50 mg ml-1) or citric acid (5-20% w/v) in a randomised procedure. Objective measurement of tussive activity was achieved using a throat microphone linked via a discriminator to a pen recorder. All four compounds produced two distinct phases of tussive activity, an early phase during challenge and a late phase 1-15 min post-challenge. Repeated challenges with PGE2, produced significant (P less than 0.01) tachyphylaxis to the late phase responses only. Both PGF2 alpha and PGE2 were approximately 1000 and 10,000 times more potent than acetylcholine and citric acid respectively for both phases of tussive activity. Tussive activity was accompanied with retrosternal soreness and tightness of the chest for PGE2, increased sputum for PGF2 alpha, and sore throats with citric acid. Although a correlation exists for man and cat with regards to the tussive potency and the early and late phases of PGF2 alpha activity no such correlation seems to exist for PGE2. The high tussive potency of the prostaglandins in man suggest that their local release in various respiratory pathophysiological conditions may be responsible for the accompanying coughs/irritancy.
Topics: Acetylcholine; Aerosols; Citrates; Citric Acid; Cough; Dinoprost; Dinoprostone; Humans; Prostaglandins; Prostaglandins E; Prostaglandins F; Tachyphylaxis
PubMed: 3865687
DOI: 10.1111/j.1365-2125.1985.tb05077.x -
British Journal of Pharmacology Sep 1977Prostaglandins E1 and E2 elevated body temperature of young chicks when injected into the hypothalamus at thermoneutrality (31 degrees C). In contrast, they lowered body...
Some effects of prostaglandins E1 and E2 and of endotoxin injected into the hypothalamus of young chicks: dissociation between endotoxin fever and the effects of prostaglandins.
Prostaglandins E1 and E2 elevated body temperature of young chicks when injected into the hypothalamus at thermoneutrality (31 degrees C). In contrast, they lowered body temperature when so injected below thermoneutrality (16degreesC): the relation of the fall in body temperature to increased heat loss and decreased heat production was examined. 2 The above effects below thermoneutrality were potentiated by pretreatment with inhibitors of prostaglandin synthetase and possible reasons for this potentation are given. 3 The O-somatic antigen of Shigella dysenteriae consistently evoked hyperthermia when injected into the hypothalamus, irrespective of whether the chicks were within or below thermoneutrality. 4 Pretreatment with prostaglandin synthetase inhibitors failed to prevent the onset of endotoxin fever; however, duration of the fever, induced by intrahypothalamic injection of the O-somatic antigen of Shigella dysenteriae was reduced. 5 The intrahypothalamic injection, belwo thermoneutrality of prostaglandins E1, E2, noradrenaline, 5-hydroxytryptamine or carbachol reversed endotoxin fever, inducing even substantial falls in body temperature. 6 While the results cast some doubts on the role of prostaglandins of the E series as mediators of endotoxin fever in chicks, they cannot be eliminated as mediators until the significance of the reduction in duration of the pyrexic response by indomethacin and 5,8,11,14-eicosatetraynoic acid, and the degree of synthesis inhibition attained, are known.
Topics: 5,8,11,14-Eicosatetraynoic Acid; Animals; Body Temperature; Carbachol; Chickens; Endotoxins; Female; Hypothalamus; Indomethacin; Injections; Norepinephrine; Prostaglandins E; Serotonin; Shigella dysenteriae; Time Factors
PubMed: 334308
DOI: 10.1111/j.1476-5381.1977.tb09737.x -
The Journal of Experimental Medicine Mar 1978Purified populations of both human peripheral blood monocytes and murine peritoneal macrophages synthesize and release Prostaglandin E in vitro. In contrast,...
Purified populations of both human peripheral blood monocytes and murine peritoneal macrophages synthesize and release Prostaglandin E in vitro. In contrast, prostaglandin E was detected in neither the supernate fluids from cultures of highly enriched human lymphocytes and granulocytes, nor in nonadherent murine peritoneal cells. Macrophage prostaglandin E production was markedly enhanced by endotoxin, and completely suppressed by indomethacin. All neoplastic monocyte-macrophage cell lines examined elaborated prostaglandin E in vitro, either constitutively or after induction with endotoxin. In contrast, prostaglandin E production could not be detected from either a T- or B-cell lymphoma, whether or not they were treated with endotoxin. These findings thus indicate that the blood monocyte and tissue macrophage represent an important source of prostaglandin E, a function shared by both normal and neoplastic mononuclear phagocytes.
Topics: Animals; Ascitic Fluid; Cell Line; Humans; Lipopolysaccharides; Macrophages; Mice; Monocytes; Polysaccharides, Bacterial; Prostaglandins E
PubMed: 632752
DOI: 10.1084/jem.147.3.952 -
British Journal of Cancer Mar 1979The effect of exogenous and endogenous prostaglandins on the patterns of growth and differentiation of Friend erythroleukaemia cells (FLC) were studied. During the...
The effect of exogenous and endogenous prostaglandins on the patterns of growth and differentiation of Friend erythroleukaemia cells (FLC) were studied. During the differentiation process, DMSO stimulated PGE synthesis by an average of 95%. The addition of a long-acting synthetic analogue of PGE2,16,16-dimethyl-PGE2-methyl ester (di-M-PGE2) to the culture medium only slightly and temporarily slowed cell growth, with no appreciable induction of differentiation. However, in the presence of DMSO, the same concentration of di-M-PGE2 produced 73% inhibition of cell growth and accelerated and potently stimulated haemoglobin production. The action of both di-M-PGE2 and DMSO on cell proliferation was dependent upon the state of cell growth at the time of the administration of these compounds. FLC cultures treated with DMSO + di-M-PGE2 produced considerable amounts of haemoglobin before even one duplication cycle was completed. Both DMSO and di-M-PGE2 stimulated endogenous PGE biosynthesis, and the biosynthetic effect of these compounds was synergistic. Inhibition of endogenous prostaglandin synthesis by indomethacin completely abolished the effects produced by DMSO + di-M-PGE2 on the growth, and substantially reduced the stimulated differentiation of FLC. These data suggest that an endogenously synthesized prostaglandin plays a significant role in both the inhibition of replication and in the stimulation of differentiation induced by DMSO and di-M-PGE2 in Friend erythroleukaemia cells.
Topics: Cell Differentiation; Cell Division; Cell Line; Friend murine leukemia virus; Hemoglobins; Indomethacin; Leukemia, Erythroblastic, Acute; Prostaglandins E; Prostaglandins E, Synthetic; Succimer
PubMed: 223618
DOI: 10.1038/bjc.1979.49