Prostaglandins, leukotrienes, and medicine最新文献

The ex vivo stability of leukotrienes (LT) C4 and D4 in human urine was tested in an experimental model. The various LTs were identified / measured by HPLC, liquid scintillation counting, RIA, UV-absorbance and GC-MS. If fresh urine was incubated under physiological conditions added LTC₄ was converted in a time-dependent manner to LTD₄ ($\text{t}\text{1}\text{2}$ about 0.5 h) and to LTE₄ ($\text{t}\text{1}\text{2}$ about 6 h), respectively. At the end of the 22 h incubation period less than 10 % of the initial LTC₄ was detectable. LTB₄ was stable under these conditions. Therefore the enzymatic urinary metabolism of LTs should be considered in experimental and clinical studies when urine is collected under different conditions.

Cultured human gingival fibroblasts were incubated with ¹⁴C-arachidonic acid (AA) at 370C for 2 hours. The metabolites formed were extracted from the cellfree medium in methanol, separated and identified by thin layer chromatography, using two solvent systems that allowed resolution of cyclooxygenase and lipoxygenase products. The predominant cyclooxygenase products were PGE2 and 6-keto-PGFl₁ PGA₂, PG_F2α, PGD₂, 15-keto-PGE₂, TXB₂ were also detected in smaller amounts. No detectable radioactivity corresponding to lipoxygenase products 5-HETE, 12-HETE, and 15-HETE was found. Incubation of fibroblasts with effervescent buffered aspirin (EBA) (.02%, .04%, .O6%), or sodium bicarbonate, citric acid and aspirin, individually, (in concentrations equivalent to those present in EBA) resulted in stimulation of synthesis of PGs except PGE₂ which was inhibited by EBA and aspirin.

The mode of action of the inhibitory effect of CPZ on 13,14-dihydroprostaglandin F2-alpha (13, 14H₂-PGF2-alpha) formation in rat ovary was examined. The inhibition of 13, 14H₂-PGF2-alpha formation and of ovulation induced by a proestrus were completely recovered by an injection of hCG (25 IU/rat) or LH-RH (500 ng/rat) at 15:00 on the same day. 13,14H₂-PGF2-alpha formation and ovulation were not inhibited by a single injection of prolactin (PRL:6 IU/rat) at 13:00 on the day of proestrus. Repeated injection of PRL inhibited cyclic ovulation and 13,14H₂-PGF2-alpha formation. The estrus cycle of PRL treated animals showed a continuous state of diestrus. Although 13,14H₂-PGF2-alpha formation and ovulation were inhibited by the repeated injection of CPZ, the repeated-simultaneous injection of CPZ and bromocriptine at 10:00 once a day for 3 days from the first day of diestrus partly restored both and entirely reversed the suppression of the cyclic-changes in the in the vaginal smear pattern.

These results indicate that the inhibition of 13,14H₂-PGF2-alpha formation induced by a single injection of CPZ probably occurs via the suppression of LH-RH release from the hypothalamus, whereas PRL secretion may participate in the inhibitory effects of repeated injections of CPZ.

The effect of calmodulin inhibitors on synoviocyte phospholipase A₂ activity was evaluated. Cells were incubated with [³H]arachidonic acid for 24 hours to label phospholipids. [³H]prostaglandin E₂ synthesis was stimulated by $\text{Salmonella minnesota}$ lipopolysaccharide (100 μg/ml). Trifluoperazine, 35 μM, reduced lipopolysaccharide-stimulated [³H]prostaglandin E₂ synthesis by 50%. In sonicated suspensions of cells, calcium-dependent phospholipase A₂ activity was inhibited by trifluoperazine 3–100 pM and by compound $\text{48}\text{80}$ (3 μg/ml). These agents inhibit calmodulin-dependent enzyme activity. The addition of calmodulin, 1 or 2.5 μM, to compound $\text{48}\text{80}\text{-}\text{treated}$ suspensions reversed this inhibition in a dose-dependent manner. Agents which inhibit calmodulin-dependent enzymes can reversibly inhibit synoviocyte phospholipase A₂ and thus prostaglandin E₂ production.

Prostanoid formation may be stimulated by different events associated with anaesthesia and operation, such as positive pressure ventilation and tissue trauma. We investigated the effects of halothane and enflurane on plasma and serum prostanoid concentrations in 19 patients scheduled for minor operations. In 9 abdominal surgery patients, thromboxane B₂ concentrations were followed up to the fifth postoperative day. Prostanoid determinations were carried out with RIA. In general, the changes in prostanoid concentrations in patients anaesthetised with halothane or enflurane were similar. During spontaneous breathing there was a decrease in plasma PGE₂ and TxB₂ concentrations. During intermittent positive pressure ventilation and operation, PGE₂ and TxB₂ concentrations rose but 6-keto-PGF_1α did not. After operation, TxB₂ concentrations remained elevated but the other prostanoids returned to preoperative values. TxB₂ concentrations decreased to the preoperative level on the first postoperative day. The elevated TxB₂ concentrations during and after surgery can be regarded, in some patients, as a potential risk factor for cardiovascular and thromboembolic complications.

The effects of bradykinin, histamine, phosphatidic acid and leukotrienes B₄ and C₄ on the distribution and release of ¹⁴C-arachidonic acid in human keratinocytes in culture were investigated. Bradykinin, histamine, and phosphatidic acid were found to liberate ¹⁴C-arachidonic acid from membrane phospholipids, whereas leukotrienes B₄ and C₄ were ineffective in this respect. The decrease in the labeling of phospholipids was accompanied by increased labeling of the non-phosphorus lipids. The present study suggests that bradykinin, histamine, and phosphatidic acid may interfere with the distribution and release of arachidonic acid in human keratinocytes in culture.

It is of great importance to clarify the role of thromboxane and prostacyclin in the process of atherosclerosis. In order to study this we induced atherosclerosis in rabbits through cholesterol feeding (1% w/w) for three to 12 weeks. After sacrifice the aorta was quickly removed and incubated. The in vitro thromboxane production measured as immunoreactive thromboxane B₂ increased by 86 per cent in atherosclerotic vessels compared to control vessels (p<0.0005). The in vitro production of prostacyclin measured as immunoreactive 6-ketoprostaglandin F₁ α showed a tendency to higher values in the atherosclerotic vessels compared to the control vessels (31%, p<0.025). This suggests that an increased thromboxane production rather than a decreased prostacyclin production might be important for the progression of atherosclerosis.

Prostaglandin (PG) levels increase dramatically just before parturition in the rat. Coincident with this dramatic increase in uterine PGs is a precipitous decrease in plasma progesterone and enhanced plasma estradiol levels. The purpose of the present study was to mimic the progesterone withdrawal phenomenon in the presence and absence of estradiol in ovariectomized pregnant rats and determine the effects on uterine PGF, PGE, thromboxane B₂ (TxB₂) and 6-keto-PGF_1a (6KF) levels. Rats were ovariectomized on gay 16 of pregnan4 and silastic inserts containing progesterone and estradiol placed s.c. in two groups of rats (I and II) while the third group (III) received progesterone only. On day 19 of pregnancy progesterone was withdrawn from groups II and III and rats sacrificed 0, 6, 12 and 24 hours later. Uterine tissue was assayed for PGs by radioimmunoassay. Progesterone withdrawal in the absence of estradiol (III) administration significantly (p< .05) elevated PGE, TxB₂ and 6KF, but not PGF, at the 24 hour period compared to controls (I). When progesterone was withdrawn in the presence of exogenously administered estradiol (II) only PGF showed enhancement (p < .05) over III at the 24 hour period thus indicating a specific effect of estradiol on the PGF metabolic pathway. In conclusion, these data indicate that: (1) progesterone withdrawal is a potent stimulus for uterine PG production and is probably a major contributor to the augmented uterine PGE, TxB₂ and 6KF levels at term in the pregnant rat; and (2) progesterone withdrawal in the presence of exogenously administered estradiol enhances uterine PGF production thus indicating a specific effect of estradiol on PGF production.

In a double-blind placebo controlled study, 25 male patients (age range: 48–67 years) suffering from peripheral vascular disease were treated daily for 4 weeks with either 2 g of calcium dobesilate (n=13) or placebo (n=12). Different platelet and prostaglandin parameters were examined before and at the end of therapy. The number of circulating endothelial cells decreased significantly (4.9 ± 2.9 to 2.0 ± 1.9; p<0,0004). In addition, a decrease in serum TXB2 was noted (p<0,0001), but no significant change in plasma TXB2. The fibrinogen half-life was shortened (p<0,0001) and the platelet half-life was prolonged (p<0,04). The level of βTG was decreased (p<0,006), but PF4 was unchanged. No alteration in the conversion of exogenous 14C-arachidonic acid by platelets to eicosanoids was observed. These observations indicate that calcium dobesilate is able to exert a favourable effect on some parameters of platelet function and prostaglandin synthesis which are important in the regulation of the hemostatic process. It is suggested that these pharmacological actions might explain, at least in part, the beneficial clinical effect of the drug.