Prostaglandins最新文献

Objective:To study the mechanism of cervical ripening by determination of prostaglandin E (PGE) and F_2α (PGF_2α) concentrations in cervical mucus during the course of pregnancy.

Study design:Cervical mucus was collected from 99 pregnant women attending the mother care unit of the department. Women with sexual intercourse within the last 24 hours before sampling and subjects with bacterial vaginosis were analysed separately.

Results:Eleven women had sexual intercourse within 24 hours before sampling. The concentration of PGE in their cervical mucus was high corresponding to 2000–4000 pg/mg w w lasting for a period of 10–12 hours postcoitally, whereas the levels of PGF_2α only increased slightly. Bacterial vaginosis was accomplished by a slight but significant elevation of PGF_2α levels but only of a minor increment of the PGE values.

The prostaglandin concentrations in the mucus from the remaining 68 women were for PGE 102.75 ± 111.51 and for PGF_2α 97.54 ± 82.48 pg/mg w w (mean ± SD). Although the values were scattered the concentrations remained at approximately the same level throughout pregnancy and there was no tendency towards an increment during the last weeks of pregnancy when cervical maturation is apparent.

Conclusion:Cervical softening seems not to be accomplished by a massive local release of prostaglandins but rather the result of a number of different mechanisms more or less influenced by minor alterations of prostaglandin synthesis and release. Involved in these mechanisms are probably neutrophil-derived collagenases. © 1997 by Elsevier Science Inc.

Prostaglandin E₁ (PGE₁, alprostadil) is a potent vasodilating agent that is frequently used to resolve cardiogenic pulmonary hypertension. To investigate the effect of PGE1 in refractory chronic heart failure in a double-blind trial, twenty patients (17 men, 3 women, 58 ± 2 years, cardiac index ≤ 2.51/min/m2, pulmonary capillary wedge pressure ≥ 20mmHg), who were in NYHA functional class IV on optimized treatment with ACE inhibitors and furosemide were infused with 30 ng/kg/min PGE₁ or placebo through 48 hours. All patients received a concomitant therapy with standardized catecholamine infusions which were given 24 hours in advance and were continued throughout the study. There was no difference in baseline values between the randomized groups before PGE₁ or placebo was added. PGE₁ resulted in decrements in pulmonary artery pressure (from 37 ± 4 to 30 ± 4 mmHg; p < 0.01), pulmonary capillary wedge pressure (from 26 ± 4 to 19 ± 3 mmHg p < 0.001) systemic vascular resistance index (from 2048 ± 213 to 1506 ± 13 dyn.sec/cm5.m2, p < 0.05) and in increments in cardiac index and stroke volume index (from 2,2 ± 0,1 to 2.8 ± 0.2 1/min. m2; p < 0.05 and from 23 ± 2 to 28 ± 2 1/m2; p < 0.05, respectively). Moreover, creatinine clearance increased (p < 0.05). Placebo infusions did not result in any hemodynamic or renal effect. Between groups percentage hemodynamic changes differed with respect to pulmonary artery pressure (p < 0.01), cardiac index (p < 0.05), stroke volume index (p < 0.05) and pulmonary vascular resistance index (p < 0.05). It is concluded that intravenous infusions with PGE₁ may add further substantial benefit to the hemodynamic state in refractory heart failure patients who are already stabilized on i.v. inotropic support with catecholamines. © 1997 by Elsevier Science Inc.

Interleukin-4 (IL-4) is a potent immunomodulatory cytokine synthesized and released by Th2 lymphocytes, mast cells and basophils. It has important effects on monocyte/macrophage cell lines, regulating the secretion of several cytokines, and the production of eicosanoids. In human monocytes and macrophages, IL-4 increases the expression of 15-lipoxygenase and 15-HETE production, but suppresses the inducible isoform of the prostaglandin H synthase (PGHS-2) enzyme and prostanoid synthesis. Prostanoids, in particular prostaglandin E₂ (PGE₂) have important functions in modulating inflammatory and fibrotic processes. We compared the effect of IL-4 on the expression of PGHS-2 in human alveolar macrophages (AM) and blood monocytes (BM) activated with physiologically distinct stimuli, lipopolysaccharide (LPS) or IL-1 in vitro. The induction of PGHS-2 mRNA and protein, and prostanoid synthesis by all stimuli was inhibited by exogenous IL-4 in both cell types. However, monocytes were more susceptible to this effect of IL-4 than alveolar macrophages. © 1997 by Elsevier Science Inc.

Thromboxane A₂ (TXA₂) is a potent constrictor of both airway and vascular smooth muscle. In addition, plasma exudation is induced in the airways by a thromboxane mimetic (U-46619). Because plasma exudation is associated with a local vasodilatation and increased local blood flow, we hypothesized that the general vasoconstrictor effect of U-46619 would be weaker in the airways than in other vascular beds, perhaps resulting in increased local airway blood flow. We studied the effects of i.v. U-46619 on blood pressure, lung resistance as well as blood flow, plasma exudation in airways and leg skeletal muscle in guinea pigs. We found (1) i.v. U-46619 increases the systemic blood pressure, blood flow in tracheal mucosa but decreases blood flow in leg skeletal muscle; (2) i.v. U-46619 induces plasma exudation in the airways, but not in the leg skeletal muscle; (3) a positive relationship between blood pressure and tracheal blood flow as well as airway plasma exudation, a negative relationship between blood pressure and blood flow in leg skeletal muscle; (4) i.v. U-46619 significantly increases lung resistance. We conclude that i.v. U-46619 induces plasma exudation in airways but not in skeletal muscle, and that this plasma exudation is associated with the increased local blood flow, which in turn is caused by increased inflow pressure and redistribution of the total body blood flow to the airways. © 1997 by Elsevier Science Inc.

Intervillous blood was collected from term placentae at delivery, and sera were tested for phospholipase A₂ under various experimental conditions. Enzyme activity was found to develop upon extended storage in the cold or at 37°C. The enzyme is reversibly inhibited by dithiothreitol, requires Ca⁺⁺ ions for activity, and tolerates various detergents. The apparent molecular weight is 42 kDa. In all these parameters the serum enzyme behaves similar to the 42 kDa phospholipase A₂ which we recently purified to homogeneity from thoroughly washed placental tissue. Serum phospholipase A₂ appears to be generated by proteolytic processing from a slightly larger inactive precursor which was detected immunochemically. Most likely this protein originates from fetal cells and may be released by membrane damage. We conclude that both placental serum and tissue harbour a novel type of phospholipase A₂ which is distinct from cytosolic and secretory phospholipases A₂. Preference for arachidonate containing substrate suggests a role in eicosanoid production within gestational tissues.

Four antiestrogens (anordiol, tamoxifen, RU 39411, ICI 182780) and the antiprogestin, mifepristone (RU 486), were administered to the following three animal models: (1) ovariectomized rats, (2) mated rats treated post-coitally; and (3) pregnant rats treated post-implantation. The antiestrogens were administered alone or in combination with mifepristone at doses effective in preventing and/or terminating pregnancy in rats. The objective of the study was to determine whether these drugs influenced uterine concentrations of prostaglandins (PGF_2α and PGE₂).

Antiestrogens administered alone to ovariectomized rats did not effect uterine PGE₂ or PGF_2α concentrations; whereas the combination of anordiol/mifepristone increased uterine PGF_2α concentration, resulting in an increase in the PGF_2α/PGE₂ ratio.

Mated rats were treated post-coitally for three consecutive days with anordiol, tamoxifen, estradiol and mifepristone alone and with the combination of anordiol/mifepristone and tamoxifen/mifepristone. An increase in uterine PGF_2α concentrations and in the PGF_2α/PGE₂ ratio occurred only in anordiol/mifepristone treated group. A decrease in uterine PGE₂ concentrations occurred in animals treated with anordiol, tamoxifen and estradiol, resulting in an increase in the PGF_2α/PGE₂ ratio.

Anordiol (5.0 mg/kg/day) and mifepristone (4.0 mg/kg/day) alone and the combination of anordiol/mifepristone (2.5/1.0 mg/kg/day) administered to pregnant rats on days 7, 8 and 9 of pregnancy induced an increase in PGF_2α levels without affecting uterine PGE₂ concentration. The changes in uterine PGF_2α concentrations induced by anordiol and the combination of anordiol/mifepristone resulted in an increase in the PGF_2α/PGE₂ ratio.

The antiestrogens tested except for ICI 182780 possessed agonist activity when assayed by measuring their capacity to increase the uterine weights in ovariectomized rats. Also, ICI 182789 was the only antiestrogen that did not influence uterine PG concentrations. It can be concluded that ICI 182780 is the only “pure” antiestrogen among those tested.

The present results show that antiestrogens and the combination of mifepristone plus anordiol at doses preventing implantation and terminating pregnancy increase uterine PGF_2α and/or decrease PGE₂ concentrations, resulting in an alteration of PGF_2α/PGE₂ ratio. These findings suggest that there exists a critical balance of PGF_2α to PGE₂ concentrations in the uterus required for the normal passage of fertilized ova through the oviduct, initiating implantation of the blastocysts, development of embryos, and maintenance of pregnancy.

The effects of phorbol myristate acetate, an activator of protein kinase C, on the release of [³H]arachidonic acid and prostaglandin synthesis were studied in an osteoblast cell line (MC3T3-E1). Phorbol myristate acetate (20 uM) liberated 16 and 55% of the [³H]arachidonate in prelabeled phosphatidylinositol and phosphatidylethanolamine, respectively, and evoked a 19-fold stimulation in the synthesis of prostaglandin E₂. Phorbol myristate acetate doubled the cellular mass of 1,2-diacylglycerol and stimulated the liberation of [³H]arachidonate from the diacylglycerol pool in prelabeled cells. The diacylglycerol lipase inhibitor RHC 80267 blocked 75–80% of the phorbol ester-promoted (total) cellular liberation of [³H]arachidonic acid and production of prostaglandin E₂. In comparison, the release of [³H]arachidonate from phosphatidylethanolamine (but not phosphatidylinositol) was only partially antagonized (to the same degree) by the PLA₂ inhibitor p-bromophenacylbromide and the protein kinase C inhibitor Et-18-OMe. PMA-induced formation of diacylglycerol or synthesis of PGE₂ was not affected by the prior inhibition of protein kinase C. Therefore, we have shown a novel pathway for the liberation of arachidonic acid in osteoblasts involving the nonspecific hydrolysis of phosphatidylinositol and phosphatidylethanolamine by phospholipase C followed by the deesterification of diacylgycerol. This pathway can be activated by a phorbol ester through a protein kinase C-independent mechanism.

$\text{Aims}$: In order to study the role of prostaglandin in the regulation of the gastrointestinal functions, gene expression of prostaglandin receptors along the rat gastrointestinal tracts were investigated.

$\text{Methods}$: Rats were used for the study. The combination of counterflow elutriation separation of mucosal cells and Northern blot analysis was used to detect the gene expression of prostaglandin receptors in gastrointestinal tracts.

$\text{Results}$: In small intestine and colon, prostaglandin E2 EP1 and EP3 receptor mRNAs were mainly localized in the deeper intestinal wall containing muscle layers. EP4 receptor gene expression, on the other hand, was detected in the intestinal mucosal layer.

In the stomach, EP1 mRNA was detected in gastric muscle layers, whereas EP3 and EN receptor gene expression was mainly present in the gastric mucosal layer containing epithelial cells. In gastric epithelial cells, parietal cells were found to have both EP3 and EP4 receptors. At lower concentrations, prostaglandin E2 inhibited gastric acid secretion by parietal cells probably through EP4 receptors. At higher concentrations, however, it stimulated it. On the other hand, mucous cells possessed only EP4 receptor mRNA.

$\text{Conclusions}$: Thus, it is suggested that prostaglandin E2 modulates gastrointestinal functions through at least three different prostaglandin receptors (EP1, EP3, and EP4), each of which has a distinct distribution in the gastrointestinal tract.

Both prostaglandins (PGs) and nitric oxide (NO) have cytoprotective and hyperemic effects in the stomach. However, the effect of NO on PG synthesis in gastric mucosal cells is unclear. We examined whether sodium nitroprusside (SNP), a releaser of NO, stimulates PG synthesis in cultured rabbit gastric mucus-producing cells. These cells did not release NO themselves. Co-incubation with SNP (2 × 10⁻⁴, 5 × 10⁻⁴, 10⁻³ M) increased PGE₂ synthesis, and SNP (10⁻³ M) increased PGI₂ synthesis in these cells. Hemoglobin, a scavenger of NO, (10⁻⁵ M) eliminated the increase in PGE₂ synthesis by SNP, but methylene blue, an inhibitor of soluble guanylate cyclase, (5 × 10⁻⁵ M) did not affect the increase in PGE₂ synthesis by SNP. 8-bromo guanosine 3′ : 5′-cyclic monophosphate (8-bromo cGMP), a cGMP analogue, (10⁻⁶, 10⁻⁵, 10⁻⁴, 10⁻³ M) did not affect PGE₂ synthesis. These findings suggest that NO increased PGE₂ and PGI₂ synthesis via a cGMP-independent pathway in cultured rabbit gastric cells.

Recently, we cloned cDNAs for the prostacyclin receptor (IP) and the four mouse PGE receptor subtypes, EPI, EP2, EP3 and EN, and established Chinese hamster ovary cells that stably express each receptor. We examined the agonist potency and selectivity of AFP-07, a 7,7-difluoroprostacyclin derivative, compared with widely used stable prostacyclin analogue, iloprost, using the cells expressing each cloned receptor. AFP-07 strongly displaced the [³H] iloprost binding to the IP receptor-expressing cell membranes, the half maximal concentration for the displacement being 3 nM, which was one order lower than that of iloprost. AFP-07 concentration-dependently stimulated CAMP formation in the IP-expressing cells, the half-maximal concentration for the stimulation being 10 pM which was one order lower than that of iloprost. On the other hand, AFP-07 showed lower affinity for EP1, EP2, EP3 and EN than PGE2, but iloprost had the same affinity as PGE₂ for the EPl. These results demonstrate that AFP-07 is a potent and highly selective agonist for the IP receptor.