Prostaglandins, leukotrienes, and medicine最新文献

Two human neuroblastoma cell lines, NCG and GOTO, were used to study the cytotoxic effect of gamma linolenic acid (GLA). The cell growth inhibition of these culture cells by GLA was found to be associated with striking membrane fatty acid modification.When culture cells were exposed to 20 μg/ml and 60 μg/ml GLA for 48 hr, polyenoic acids in cell membrane phospholipids (PC, PE, PI, PS) and triglyceride significantly increased; 1.8–21.0 fold for NCG and 1.04–11.5 fold for GOTO, in association with decreased monoenoic acids. The most remarkable changes were; increase of C18:3, C20:3, C20:4 and decrease of C18:1. CoQ₁₀ (50 μg/ml) and vitamin E (10 μM) shown to protect against the cytotoxic effect of GLA did not modify the incorporation of GLA into tumor cells.

These results indicate that the antitumor effect of GLA is probably due to cellular dysfunction caused by fatty acid modification after GLA incorporation.

The effects of 3-dimethylamino 5-(3′ trifluoromethylbenzylidene) 6-methyl (4H)-pyridazine (PC88) on the biosynthesis of PGI₂, using horse aorta microsomes as a source of enzyme and arachidonic acid as a substrate, were investigated. Under the experimental conditions adopted, PC88 was shown to dosedependently inhibit PGI₂ biosynthesis (ID50 = 6.9×10⁻⁴ M ± 1.87 × 10⁻⁷ M). This inhbitory effect of PC88 was complex: it was of neither competitive nor non-competitive type. 3-dimethylamino 5-(2′,6′-dichlorobenzylidene 6-methyl-(4H)-pyridazine (PC89) enhanced the biosynthesis of PGI₂. It is worth noticing the replacement of the 2 Cl at carbon atoms 1 and 4 by a CF₃ at carbon atom 2 of the phenol ring. This appears to reverse the activity of the molecule on the synthesis of PGI₂. PC88 and PC89 were both inhibitors of TXA₂ synthetase.

Human decidua was obtained from nonlaboring women after elective cesarean section. Decidua was incubated with media alone for 20 hours and this media (decidual conditioned media) was then incubated with amnion cells in monolayer culture and amnion rings. A 90% decrease in PGE2 production by amnion cells in monolayer culture was demonstrated in the presence of decidual conditioned media when compared to controls. In short term incubations with fresh amnion, decidual conditioned media decreased the production of PGE2 in amnion by greater than 25% of the control rate of production in 17 of 21 experiments. These observations suggest that human decidua produces a factor capable of inhibiting prostaglandin production by amnion.

In view of existing reports documenting that “in vitro” norepinephrine (NE) contracts ring-shaped rat aortic preparations, whereas it relaxes arterial strips mounted in longitudinal fashion within an organ bath: it was decided to explore possible reasons which may account for such disparate: actions of the same ogonist on the same tissue. Isolated rings (circular preparations) obtained from rat thoracic aortae responded to increasing concentrations of NE with dose-dependent tonic enhancement, not significantly affected by the presence of indomethacin (10⁻⁶M); whereas, preincubation with phentolamine (10⁻⁶M), yohimbine (10⁻⁷M)or prazosin (10⁻⁸M), shifted significantly to the right points of the positive inotropic dose-response curve for NE. On the contrary longitudinally mounted preparations of rat aortic stips, reacted to increasing concentrations of NE with dose-dependent relaxation, an effect not modified by the presence of a beta-adrenoreceptor blocker, namely propranolol (10⁻⁶M). However, in presence of alpha-adrenoreceptor blockers, such as phentolamine (10⁻⁶M), yohimbine (10⁻⁷M) or prazosin (10⁻⁸M), the negative inotropic dose-response curve for NE was shifted to the right whereas in the pres nce of indomethacin (10⁻⁶M) or of tranylcypromine (2.5×10⁻⁴M), the NE-induced relaxation was either abolished or significantly displaced to the right, respectively. In another series of experiments the generation of labelled 6-keto-prostaglandin F₁ α(the most important non-enzymatic metabolite of prostacyclin) by chopped rat aortae incubated for one hour with (1-¹⁴C)-arachidonic acid, was explored and found to be significantly enhanced by the delivery of NE (3 × 1O⁻⁶M). The present evidence suggests that NE acting on alpha-adrenoreceptors, induces in longitudinal and in chopped arterial preparations, but not in aortic rings, an inhibitory relaxing factor, presumably produced by the endothelium. This factor is probably prostacyclifor the relaxing effects of the agonist were negatively influence by indomethacin and by tranycypromine, two known antagonists of PGI₂ formation. In vascular rings (circular arterial preparations) the tonic stimulatory action of NE (not affected by preincubation with indomethacin) was the only evident inotropic effect of the agonist presumably because the extensive handling of the tissue as well as the anchoring procedure followed to mount arterial preparations within the bath for contractile recordings, may produce de-endothelization. Moreover, the notion is advanced that the apparently greater aortic prostacyclin synthesis after NE in preparations with better preserved integrity may represent a local modulating mechanism, controlling vascular responses to sympathetic activation.

The primary stimulus for compensatory renal growth is unknown. This process may be regulated by a circulating renotropic factor or may reflect a growth response to increased work. Prostaglandins appear to participate in compensatory renal growth as indomethacin has been shown to attenuate increases in both renal mass and function after uninephrectomy in rats. The goal of the present study was to test the effects of other cyclooxygenase inhibitors on compensatory renal growth and to evaluate the effects of indomethacin on renal growth $\text{in vitro}$ in response to the purported renotropic factor. Both ibuprofen and meclofenamate retarded compensatory renal growth two days after uninephrectomy in rats (p<0.05). The addition of indomethacin to the medium of kidney slices incubating with sera from uninephrectomized rats reduced renal DNA synthesis, whereas indomethacin had no effect on renal growth when added to slices incubating with sera from intact animals. These data provide more support for an important role for prostaglandins in compensatory renal growth.

Clonidine and paraaminoclonidine prevented the formation of indomethacin-induced gastric ulcers in female rats. This protective activity was blocked by coadministration of yohimbine. Therefore, the antiulcer activity of clonidine was due to its peripheral alpha-2 agonistic action. Because indomethacin is a prostaglandin synthetase inhibitor, its ulcerogenic effect has been attributed to a state of prostaglandin (PG) deficiency. We therefore investigated the possibility that the protective effect of alpha-2 adrenoceptor agonists could be mediated by stimulation of the biosynthesis of PGs in the stomach. However, the results failed to show incresed production of PGE₂ or 6-keto-PGF1, either in stomach slices $\text{in vitro}$ or in the gastric mucosa of rats pretreated with clonidine, whether indomethacin was used or not. It is concluded that the activity of clonidine in preventing indomethacin-induced gastric erosions in rats is probably not related to prostaglandins.

The in vitro effects of obstetric drugs on 15-hydroxyprostaglandin dehydrogenase activity were investigated. Enzyme activity was inhibited by indomethacin, methylergometrine maleate, Solcoseryl®, conjugated estrogen and progesterone, and was activated only by isoxsuprine-HCL. Methylergometrine maleate and isoxsuprine-HCl, which have opposite functions on uterine muscle, also exerted contrary effects on enzyme activity. Inhibitory and stimulatory effects of these drugs suggested that they could directly regulate uterine activity and also indirectly influence the uterus due to their effects on prostaglandin catabolism in vivo.

In order to further elucidate the mechanisms involved in therapeutic effects of prostacyclin and Iloprost in peripheral ischemic disease, the actions on microvascular tone, capillary density, and increases in venular permeability induced by inflammatory mediators and by ischemia were investigated in the cheek pouch of anaesthetized Syrian hamsters using intravital videomicroscopy and - for quantification of vascular permeability - venular leakage of fluorescein-labelled dextran (FITC-D; Mw 70,000). Iloprost at the nonhypotensive, platelet aggregation-inhibiting dose of 0.5 μg/kg/min i.v. significantly increased the diameters of arterioles and venules and the density of perfused capillaries and antagonized vasoconstriction and decrease of perfused capillary density as induced by Leukotriene D₄ (LTD₄; 10⁻⁷ M). Iloprost significantly antagonized venular leakage of FITC-D induced by histamine (10⁻⁵ M), serotonin (10⁻⁵ M), bradykinin (10⁻⁶ M) and reperfusion after 30 min ischemia. Topical application of Iloprost (10⁻⁸ M), intraarterial infusion of Prostaglandin E₁ (PGE₁; 2.0 μg/kg/min), and topical Forskolin (10⁻⁵ M) also attenuated histamine-induced venular FITC-D leakage, while topical PGE₁ (10⁻⁷M) and i.v. infusion of Nifedipine (30 μg/kg + 10 μg/kg/min) were not effective.

It is concluded, that microvascular effects of Iloprost by improvement of tissue perfusion and functional antagonism of mediator-induced tissue edema and vasospasm could contribute to therapeutic effectiveness in ischemic diseases.

Platelets and neutrophils are important in determining the extent of myocardial injury following coronary occlusion. The detrimental effects of these blood elements are mediated in part via release of arachidonate metabolites and oxidative species. A new selective inhibitor of leukotriene formation, piriprost (U-60,257), has been observed to decrease both neutrophil accumulation in the myocardium and infarct size following coronary ligation in experimental animals. Since piriprost may have clinical use, we examined its effects on human platelet and neutrophil functions. This compound was found to exert potent inhibitory effects on epinephrine-induced human platelet aggregation and TXA₂ biosynthesis (IC₅₀ 0.04μM). Piriprost also inhibited human neutrophil chemotaxis, oxidative species release, aggregation, and LTB₄ synthesis with IC₅₀ of 0.1, 0.04, 10 and 14 μM, respectively. Thus, piriprost inhibits a variety of human platelet and neutrophil functions. Because of its suppressive effects on human platelet and neutrophil functions and protective effects in experimental myocardial infarction, this agent may have clinical applications.