Prostaglandins, leukotrienes, and medicine最新文献

High doses of dexamethasone (1–12 mg/kg twice daily) were administered to pregnant rats for 2 days. The effect of dexamethasone on fetal and maternal lung prostaglandin metabolism was examined on day 21 of gestation. Dexamethasone treatment at all dosages significantly increased conversion of [¹⁴C]-arachidonic acid to 6-ketoprostaglandin F_α in both fetal and maternal lung homogenates. This finding is similar to our earlier finding using lower dosages of dexamethasone and suggests that dexamethasone enhances lung prostaglandin synthetase activity. Because dexamethasone is known to inhibit the activity of phospholipases, we also measured lung immunoreactive 6-ketoprostaglandin F_α. The results showed that dexamethasone treatment did not diminish lung 6-keto-prostaglandin F_1α level even at the highest dosage used (12 mg/kg). These results suggest that high dosages of dexamethasone, such as those used in the clinical treatment of septic shock, do not inhibit synthesis of lung prostaglandin.

The effect of D-penicillamine (DPA) on immunoreactive prostanoid concentrations was studied in a primary culture of adherent synovial cells from patients suffering from rheumatoid arthritis (RA). DPA in clinically achievable concentrations increased the levels of prostaglandin E₂ (PGE₂) and thromboxane B2 (TXB₂) and reduced those of 6-keto-prostaglandin F_1α (6-keto-PGF_1α) synthetized from endogenous substrate. The capacity for PGE₂ and 6-keto-PGF_1α production in the presence of exogenous arachidonic acid was decreased by DPA. These effects may be connected with the antirheumatic and immunosuppressive action of DPA.

Ischemia was induced for 25 min in the spinal cord of rabbits followed by a long term period of recirculation. At various time points of recirculation (5, 30 min, 4, 18 hr and 1 wk) slices were taken from the ischemic region and incubated for 45 min in Krebs-Ringer solution. The levels of the eicosanoids, PGE₂, PGD₂, PGF_2α, TXB₂, 6-keto-PGF_1α and 5-HETE accumulated in the incubation medium were measured by radioimmunoassay.

TXB₂ release was found to be increased at an early (5 min) and late (1 wk) period of reperfusion. A seven-fold increase in the release of 5-HETE was found 5 min after reperfusion that tended to stay elevated at 18 hr and 1 week of recirculation. PGI₂ synthetase activity decreased by 40% at 30 min, with return to normal at later time points. The ratio of TXA₂/PGI₂ was significantly higher than control at 30 min and 1 wk. T e synthesis of PGE , PGD₂ and PGF_2α was maintained at normal levels throughout the complete course of reperfusion. No changes in eicosanoid synthesis were noted in remote spinal cord regions.

The significant increase of TXA₂ synthesis at 5 min and 1 wk of reperfusion may point to a role of this arachidonate metabolite in the acute events and in the later stages of neurological dysfunction. The enhanced release of 5-HETE, a metabolite of 5-HETE, suggest an enhanced formation of leukotriene B₄ and peptide leukotrienes and a potential role for these 5-lipoxygerase metabolites of arachidonate in ischemia injury to the brain and the spinal cord.

To determine the effect of anti-neoplastic chemotherapy on the vascular system(s) of children with leukemia/lymphoma, urinary excretion of 6-keto-PGF_1α was measured by radioimmunoassay (RIA).

In 4 patients receiving therapy, 6-keto-PGF_1α increased to a mean of 148 (range; 126–170)% during therapy, la increased returned to pre-treatment level 3–5 days later. In 18 long-term survivors who had completedtherapy, 6-keto-PGF_1α was determined to be a meanof 275 (range; 52–905) ng/g creatinine, and in the healthy control children the mean was 146 (range; 71–348) ng/g creatinine. These results were contrary to our hypothesis that chemotherapy might cause a decreased synthesis of PGI₂, a precursor of 6-keto-PGF_1α, and suggest that increased urinary 6-keto-PGF_1α reflects a vascular response to acute exposure to chemotherapeutic drugs and possible vascular damage due to long-term intensive chemotherapy in pediatric patients with leukemia/lymphoma.

In spontaneously hypertensive (SHR) and normotensive rats (WKY), diets supplemented with n-3 fatty acids of different chain length (α-linolenic acid, LNA - C 18:3, n-3 with linseed oil and eicosapentaenoic acid, EPA - C 20:5, n-3 with cod liver oil) were fed over a period of 22 weeks. A diet with commercially available pellets served as control. After the LNA-rich diet the augmentation of LNA was most pronounced in liver triglycerides (TG) and free fatty acids (FFA), whereas the increase of EPA was most marked in phosphatid.lethanolamine (PE) and phosphatidylcholine (PC) when compared with the controls. Docosahexaenoic acid (DHA) was decreased mainly in neutral lipids. Of the n-6 fatty acids linoleic acid (LA) appeared significantly depressed in TG and FFA, but increased in phospholipids. Arachidonic acid (AA), however, was lower in all lipids.

In SHR and WKY fed the EPA-rich diet EPA and DHA were significantly higher as compared to the controls on a pellet diet. On the contrary, INA was not detectable in all lipid classes. LA and AA were markedly depressed. Docosenoic acids were significantly increased. The P/s-ratio did not reflect the changes in the 20:5/20:4- and n-3/n-6-ratios. The data indicate a differential effect of dietary n-3 fatty. acids of different chain length on the supply of other n-3 fatty acids. Moreover, after an LNA-rich diet divergent alterations of LA in neutral lipids and phospholipids occurred. The results are dissimilar to those obtained in adipose tissue. Blood pressure was not influenced by the diets in either SHR or WKY. SHR or WKY.

The intra-uterine administration of actinomycin D on Day 10 reduced the output of prostaglandin (PG) F_2α (the major PG released) from the Day 15 guinea-pig uterus $\text{in vitro}$ by 80 to 85%. PGE₂ output was reduced by 50%, while 6-keto-PGF_1α output was unaffected. Plasma progesterone levels were high (3 to 15 ng/ml) on Day 15 due to the reduction in uterine PGF_2α output. Endometrial PGF_2α synthesizing capacity was reduced by 50% by actinomycin D treatment, while endometrial PGE₂ and 6-keto-PGF_1α synthesizing capacities were unaffected. Oestradiol treatment $\text{in vivo}$ did not reverse the inhibitory effects of actinomycin D on uterine PG production.A23187 increased uterine PGF_2α, 6-keto-PGF_1α and PGE₂ outputs irrespective of treatment, indicating that substrate supply was always rate limiting. Actinomycin D inhibited the uterotrophic action of oestradiol indicating that fresh protein synthesis had been inhibited. Overall, this study suggests that increased protein synthesis is involved in stimulating endometrial PGF_2α synthesis and release.Previous studies have shown that increases in enzyme activities induced by oestradiol are only secondary events in the stimulation of endometrial PGF_2α production. We propose that oestradiol induces the synthesis of a protein (‘lipostimulin’) which, acting on a progesterone-primed uterus, “switches on” endometrial PGF_2α synthesis and release by causing the activation of endometrial phospholipase A₂.

The present study suggests that a diminished level of HDL is connected with an enhanced susceptibility to arrhythmogenic stimuli only in rats pretreated with a diet deficient in polyunsaturated fatty acids (PUFA), but not after a PUFA-rich or pellet diet. The endogenous level of total cholesterol did not influence the thresholds for ventricular flutter or ventricular fibrillation in aconitine-induced arrhythmia in rats or in ouabain-induced arrhythmia in guinea pigs.

The possibility that lymphokine-activated killer (LAK) cells versus spontaneous natural killer (NK) cells show relative resistance to the suppressive effects of the immunoregulatory molecules prostaglandin E₂ (PGE₂) and dexamethasone (DMO) was investigated. LAK cells were produced $\text{in vitro}$ by the incubation of human peripheral mononuclear cells (PBMC) for three days in the presence of interleukin-2 (IL-2). Cytotoxicity of NK and LAK cells were measured by conventional 4 hour Cr⁵¹ release assays using K562 and Daudi target cells. LAK cells were relatively resistant to suppression by PGE₂. For example, NK cytotoxicity was significantly suppressed by 10⁻⁶ M PGE₂. In contrast, LAK cells required a 30 to 100 higher concentration of PGE₂ according to the target used to achieve similar suppression. Likewise, a differential resistance to DMO was seen. NK cells were significantly suppressed by 10-³M DMO while a 1000 fold higher concentration was needed for similar suppression of LAK cytotoxicity. Overall, the results show that LAK cells are relatively resistant to immunoregulatory suppressive factors.

The levels of 11-deoxy-13,14-dihydro-15-keto-11β,16ζ-cyclo prostaglandin E₂ (bicyclo PGEM), 13,14-dihydro-15 keto-prostaglandin F_2α (PGFM) and prolactin were measured in four serial plasma samples collected from thirty women undergoing therapeutic abortions in the first trimester by a suction curettage procedure. Eleven of these women received a preoperative loading dose of sodium meclofenamate, a PG synthetase inhibitor, before the abortion procedure was started and the rest received this medication after the last blood samples were drawn. Prolactin levels increased significantly during the procedure. Sodium meclofenamate treatment had no effect on this increase. Bicyclo PGFM levels did not increase during the procedure in untreated or treated women, whereas PGFM levels increased but only in untreated women. The lack of increase in treated women apparently was not a treatment effect because PGFM levels in corresponding samples of untreated and treated women were similar. Treatment significantly reduced the bicyclo PGEM levels immediately after completion of the procedure as compared to untreated women. This differential PG response to treatment is unprecedented and may be due to sodium meclofenamate inhibition of PGE₂ and not PGF_2α synthesis. Nevertheless, these data demonstrate that sodium meclofenamate treatment of patients undergoing first trimester therapeutic abortion to relieve pain involves selective suppression of PGE₂ synthesis.