Prostaglandins, leukotrienes, and medicine最新文献

The formation of arachidonate lipoxygenase products by uterine and intrauterine tissues of sheep in the last third of gestation has been evaluated. Maternal and fetal cotyledon, myometrium and fetal membrane exhibited evidence of arachidonate 5-, 12-, and 15- lipoxygenase activities. The major lipoxygenase product formed by fetal membrane and fetal cotyledon was leukotriene B₄ (LTB₄) whereas maternal cotyledon and myometrium produced mainly 12-hydroxyeicosatetraenoic acid (12-HETE). Arachidonate lipoxygenase products may play significant roles in the regulation of fetal and uteroplacental hemodynamics and it is speculated that the formation of leukotriene B₄ predominantly by tissues of fetal origin may be of significance in the immunologic adaptations of pregnancy.

Repeated subcutaneous (SC) injections of mercuric chloride (MC) in Brown Norway (BN) rats induce an autoimmune glomerulonephritis (GN) due to antiglomerular basement membrane (BM) antibody deposition in the glomeruli. The aim of this study was to investigate the effects on MC-induced autoimmune GN of a) OKY-046,a selective TXA-synthetase inhibitor b) herring oil (HO), which is rich in eicosapentaenoic acid (EPA) (5.6%) precursor of the three series of prostaglandins (PGs) and of (inactive) thromboxane (TXA3),and c) evening primrose oil (EPO), which is rich in linoleic acid (LA) (72%) and gamma-linolenic acid (GLNA) (9%), precursors of the one series of PGs, mainly PGE1,and of (inactive) TXA1. The administration of OKY-046 significantly inhibited proteinuria, partially prevented fibrin thrombi (FT) formation in the glomeruli, decreased urinary TXB, enhanced 6ketoPGF excretion and, increased survival rate of the animals from 60% (group receiving only MC) to 86%. However, OKY-046 did not prevent body weight (BW) loss or the development and deposition of IgG in the glomeruli. Increased intake of HO (80 days prior and throughout the experiment) and avoidance of arachidonic acid (AA) intake prodused an effect comparable to that of OKY-046 in the rats. Furthermore, HO significantly inhibited the deposition of IgG in the glomeruli, increased the survival rate of the animals to 100% and further enhanced the increased urinary PGE excretion indused by MC. However, HO did not prevent BW loss in the animals. Increased intake of EPO and avoidance of AA intake prodused an effect comparable to that of HO. Additionally, EPO completely prevented BW loss induced by MC in these animals. These findings suggest that the metabolites of AA, EPA and GLNA play an important role either in the development or in the modulation of this model of MC indused GN.

The effect of different dietary lipid supplements on the contractility and susceptibility to isoprenaline-induced dysrhythmia in rat papillary muscles was examined after one year's prefeeding of either a low fat (4%, w/w) standard laboratory diet or those supplemented with additional (12%, w/w) saturated animal fatty acids (sheep perirenal fat; SF) or n-6 or n-3 polyunsaturated fatty acids (PUFA's) from sunflower seed oil (SSO) or tuna fish oil (FO) respectively.

The positive inotropic response to Ca⁺⁺ and the incidence of spontaneous tachyarrhythmias under isoprenaline load were significantly less in the muscles from SSO and FO fed animals compared to either mature REF or SF fed groups. Indomethacin reduced the response to Ca⁺⁺ in both the REF and SF groups, but was without effect upon the muscles from SSO and FO groups. In addition this drug also significantly reduced isoprenaline-induced dysrhythmia in the muscles from REF and SF fed animals, but had no effect upon those from SSO and FO groups which were already less suceptible to dysrhythmia than the muscles from animals in the former two groups.

These results indicate that “$\text{long-term}$” feeding of either n-3 or n-6 PUFA's can significantly reduce arrhythmogenesis in this species $\text{in vitro}$ by mechanisms that may involve eicosanoid metabolism.

The generation and metabolism of leukotrienes (LTs) from polymorphonuclear granulocytes of four polytraumatic patients on stimulation with the Ca-Ionophore A 23187 were studied by high performance liquid chromatography. In contrast to healthy donors the concentration of LTB₄ within the supernatant of the stimulated granulocytes from these patients is reduced. The ratio of LTB₄ versus the combined amounts of the biologically inactive 6-trans and 12-epi-6-trans-isomers is significantly decreased. In one patient who suffered from an Adult Respiratory Distress Syndrome (ARDS) a pronounced enhancement of LTC₄ synthesis was observed.

Prenatal maternal glucocorticoid treatment has been reported to reduce the incidence of patent ductus arteriosus in prematurely born infants. Patency of the ductus arteriosus is thought to be maintained primarily by the vasodilatory effect of PGE, both in utero and in prematurely born infants, and lung is a major source of PGE, in fetuses and neonates. 15-Hydroxy-prostaglandin dehydrogenase (15-PGDH) catalyzes the initial reaction in converting biologically active PGE, to its inactive analogue, 15-keto-PGE₂. In the present study, effect of prenatal dexamethasone treatment on the activity of fetal rat lung 15-PGDH was studied at 20, 21 and 22 days of gestation.

Activity of fetal lung 15-PGDH more than doubled from 20 to 22 days of gestation. Dexamethasone treatment at 0.4 mg/kg and 0.8 mg/kg significantly increased the activity of 15-PGDH in both 20- and 21-day fetuses but had no effect on 2 22-day fetuses. We speculate that the clinical observation that prenatal glucocorticoid treatment reduces the incidence of patent ductus arteriosus in premature infants say in part be due to the stimulatory effect of glucocorticoid-on the activity of 15-PGDH in fetal and neonatal lung and possibly other organs.

In in vitro experiments on the oviduct of the domestic hen LTC₄ and LTD₄, in a dose range from 1.10⁻¹⁰ to 1.10⁻⁶ M/1, significantly stimulated the motility of all oviductal parts. With the lower doses, however, vaginal motility was suppressed (p < 0.05). In vivo experiments on the anesthetized bird i.v. bolus injections of LTC₄, 1, 3, and 10 μg/hem induced transient intrauterine pressure rises of up to 7±1 mm H₂O. In the conscious animal i.v. bolus injections of LTD₄, 10 μg/hem, resulted in a shortlasting increase in uterine myoelectrical activity (p <0.001), whereas vaginal and duodenal myoelectrical activities were inhibited. Intrauterine injections of 10 μg LTD₄, however, had neither a significant effect on myoelectrical activity of the empty uterus nor induced premature oviposition. These experiments demonstrate for the first time that LTs exert pronounced effects on in vitro motility of the hens oviduct. The in vivo responses however, are rather unimportant regarding as well strength as duration.

Activated components of the complement system have been shown to stimulate the arachidonic acid cascade. We have reported that hepatic thromboxane production in response to plasma activated with zymosan is self-limiting, not affected by nifedipine, but inhibited by mepacrine, a phospholipase inhibitor. To further study this relationship, we have tested the effects of dantrolene sodium, an agent reported to immobilize intracellular calcium. Control group livers were perfused with Krebs-Henseleit bicarbonate buffer at a rate of 120 ml/min in a nonrecirculating perfusion system and administered 1 ml/min of normal rabbit plasma for 10 minutes. This group of livers demonstrated stable wet weight, perfusion pressure, and rates of release of lactic dehydrogenase, thromboxane B₂, and prostacyclin over a 150 minute experimental period. In contrast, the administration of 1 ml/min of zymosan-activated plasma resulted in significant increases in the rate of thromboxane B₂ release at 1, 3, and 5 minutes after the start of the infusion. The rate of thromboxane production then returned to baseline values. Neither prostacyclin nor lactic dehydrogenase release changed significantly after ZAP. A similar change in thromboxane production following ZAP administration was seen in livers being continually perfused with 10 μM dantrolene sodium. Perfusion pressure was significantly elevated in this group during the ZAP infusion period. These results confirm complement-mediated thromboxane production in the isolated rabbit liver model but do not describe a definitive role of dantrolene-sensitive intracellular calcium release in the mechanism of ZAP-mediated thromboxane production.

Macrophages, isolated from dialysis fluid of three patients with continuous ambulatory peritoneal dialysis (CAPD) at different times during peritonitis were labelled with ¹⁴C-arachidonic acid and stimulated with the calcium ionophore A23187. The main metabolites formed by 5-lipoxygenase activity were leukotriene B₄ (LTB₄) and 5-hydroxy-6,9,11,14-eicosatetraenoic acid (5-HETE). Smaller amounts of cyclooxygenase metabolites were present and also a major compound with an elution time between 6-keto-prostaglandin F_1α (6-keto-PGF_1α and thromboxane B₂ (TxB₂). This substance was isolated, analysed by GC-MS and identified as 20-hydroxy-leukotriene B₄ (20-OH-LTB₄). This indicates that human peritoneal macrophages obtained from CAPD not only produce leukotrienes and prostaglandins, but also the ω-hydroxylase product of LTB₄, which has been demonstrated to be present in polymorphonuclear leucocytes. The activity of this enzyme was not correlated with the severity of the peritonitis.

The existence of diurnal variation in renal function is well described. Prostaglandins are intimately involved with renal physiology, yet a diurnal variation in their excretion is not well documented. We collected 12 consecutive 2 hour urine specimens from 10 young healthy females and measured prostaglandin E2 [PGE2], thromboxane B2 [TXB2], and 6-keto-prostaglandin-F1-alpha by radioimmunoassay for each specimen. We also measured urine volume, urine sodium, and urine creatinine levels. Regression analysis was used to determine the best sine curve for time versus each set of mean values. Only the urinary excretion of PGE2 and TXBZ, as well as water were found to significantly fit the generated sine curves. The curves for PGE2 and TXB2 showed a temporal dissociation in their peak and trough values. The excretion of PGE2 between 0800 hours and 2000 hours was significantly higher than during the hours of 2000 and 0800. The opposite was true for the TXB2 excretion. This data suggests that these two prostaglandins and water are excreted in a sine wave pattern. It also suggests that the excretion of PGE2 and TXB2 may respond to different time associated stimuli. We also showed a significant correlation between PGE2 excretion and both the excretion of water and sodium.

Previous work has shown repeated low doses of flunixin meglumine (FM) inhibit thromboxane production in normal horses. Enhanced concentrations of thromboxane in serum occurred after the drug therapy was discontinued. Our study was performed to evaluate the effects of low doses of FM in horses repeatedly challenged with endotoxin. Group I horses received E. coli endotoxin (0.1 μ g/kg IV) at 0 and 90 h. Group II horses received endotoxin and were also treated with FM (0.25 mg/kg IV) at 2, 10, 18, 26, 34, and 42 h after the initial administration of endotoxin. Clinical signs of endotoxemia were observed in all horses, but FM treated horses recovered more rapidly. The leukopenic response after endotoxin was attenuated in Group II following the second dose.

Serum thromboxane (TxB₂) decreased after the initial administration of endotoxin and remained below baseline values throughout the study. Serum TxB₂ concentrations were not different between the groups. Plasma TxB₂ and 6-keto-PGF_2α concentrations were increased after the initial endotoxin injection. In Group II, plasma TxB₂ levels declined rapidly after FM administration and remained low. After the second dose of endotoxin, Group I horses had a mild rise and decline in TxB₂ and 6-keto-PGF_2α concentrations, respectively. Thromboxane B₂ levels in Group II changed little after the second dose of endotoxin, but a dramatic increase in 6-keto-PGF_2α concentrations occurred. These results suggest that multiple low doses of FM to horses with endotoxemia cause a selective and sustained suppression of TxB₂ production and an enhancement of 6-keto-PGF_2α.