Prostaglandins, leukotrienes, and medicine最新文献

There have been conflicting reports on the effect of non-steroidal anti-inflammatory drugs on the abortifacient effect of prostaglandins. The efficacy of intra-amniotic 1.5 mg 15(S)15 methyl PGF_2α (15 me PGF_2α) in terminating mid-trimester pregnancy in 10 subjects has been compared with the effect of the same medication given to 10 others who had had indomethacin 25 mg and 50 mg orally three and one hour before the PG administration. In the subjects who had the PG analogue only the injection-abortion interval was,17.0 hours. This was significantly shorter (P < 0.01) than in those who had also received indomethacin (25.4 hours).

Leukotriene B₄ release from polymorphonuclear granulocytes of severely burned patients was reduced as compared to healthy donor cells. This decrease is due to an enhanced conversion of LTB₄ into the 20-hydroxy- and 20-carboxy-metabolites and further to a decreased LTB₄-synthesis. In addition, studies on the exogenous LTB₄-conversion revealed an unidentified compound which was derived from LTB₄. Our data suggest a modulation of the enzymatic activities involved in ω-oxidation of LTB₄ (isoenzymes of cytochrome P-450).

This study was aimed at investigating systemetically the aggregation of human gel filtered platelets induced by various physiological stimuli such as thrombin (0.25 U/ml), collagen (2 μg/ml), a mixture of thrombin and collagen, and ADP (2–5 μM). For quantitative measurement of TXB2, PGF2a and 12-HETE, negative ion chemical ionization - gas chromatography/mass spectrometry using stable isotope dilution was applied. Stimulation by thrombin, collagen and the combined agonists resulted in an increase of TXB2 (up to 54 ng/1 × 10⁸ platelets) and 12-HETE (up to 44 ng/1 × 10⁸ platelets) during platelet aggregation. The simulation with ADP showed only little increase of these metabolites and this only during the second wave of aggregation. Very little amounts of PGF2α were produced during thrombin stimulated aggregation.

A ninhydrin positive compound (L2) from commercially available unfermented dry green tea (Thea sinesis) leaves is found to be a potent inhibitor of thrombin-stimulated thromboxane formation in rabbit whole blood. Its potency is compared with caffeine, a member of the methylxanthines family. Both caffeine and L2 inhibit thromboxane formation in whole blood in a dose dependent fashion. L2 inhibition when calculated as I₅₀by a dose response curve is found to be more than 40 fold stronger tan caffeine as an inhibitor of thromboxane formation.

A concentration of L2 as low as 50 μM, supresses thromboxane formation (by 84%) whereas a concentration of 5000 u M is necessary to achieve the same inhibiton with caffeine. The potent inhibitory effect of L2 on the TXB₂ production maybe of benefit in the treatment of vascular disease.

The present study describes the effect of 16,16-dimethyl prostaglandin E₂ (16,16-dmPGE₂) on mucus glycoprotein biosynthesis in rat stomach and duodenal glands. After in vivo treatment with 16,16-dmPGE₂ (10 μg/kg subcutaneously) for 1 h, the incorporation rate of [³H]galactose, [^3H]glucosamine, and [^3H]serine in the $\text{ex}$ $\text{vivo}$ vascularly perfused stomach was determined by light microscopic autoradiography.

As was previously found by us for the surface mucous cells in the fundus of 16,16-dmPGE₂-treated rats, the incorporation of [³H]galactose and [^3H]glucosamine (indicative of mucus glycoprotein synthesis) in the isthmus was increased two- to fourfold. Small if any increases were detected in the mucous cells near the base of the glands of the fundus (neck cells), the mucous cells in the antrum and the mucous cells in the duodenal glands. Total protein synthesis as measured by [^3H]serine incorporation was not increased in any of these cells.

We conclude that 16,16-dmPGE₂ has different effects on mucus glycoprotein biosynthesis in various regions of the rat stomach. Increased biosynthesis in the fundus points to a role for mucus in the prostaglandin-induced protection of the gastric mucosa against injury.

The effects of indomethacin on vascular resistance were investigated in the feline mesenteric vascular bed under conditions of constant blood flow. Indomethacin produced mesenteric vasoconstriction that was dose-dependent but was less active than U46619, the thromboxane mimic, angiotensin II, PGF_2α and norepinephrine. The vasoconstrictor response to indomethacin was not altered by meclofenamate and phenoxybenzamine. Indomethacin, in a dose that blocked the systemic vasodepressor response to arachidonic acid, did not alter mesenteric vasoconstrictor responses to sympathetic nerve stimulation, norepinephrine, angiotensin II, U46619, and U44609. The present data suggest that in the feline intestinal vascular bed indomethacin has marked vasoconstrictor activity that occurs independent of activation of alpha-adrenoceptors and formation of cyclooxygenase products possessing pressor activity. The present data suggest that cyclooxygenase products do not modulate vasoconstrictor responses as well as the sympathetic nervous system in the intestinal vascular bed of the cat.

We investigated the involvement of arachidonic acid metabolites in basal and thyrotropin releasing hormone (TRH) stimulated prolactin release by GH₃ cells, a cloned strain of rat pituitary tumor cells.

GH₃ cells spontaneously released 9 and 154 HETEs and the 15 HETE release was greater than that of 9 HETE. When the cells were challenged by 10⁻⁵M AA, they were able to produce 5, 9, 12 and 15 HETEs. 10⁻⁶M TRH only stimulated the release of the two metabolites synthesized by the basal cells (15 and 9 HETEs). This release depended on the length of stimulation by TRH. When both AA and TRH were added, there was an increase in 15 and 9 HETE production. In all cases, more 15 HETE was released than other metabolites.

In dose-response studies using TRH concentrations of 10⁻⁶M to 10⁻¹²M, the highest level of 9 HETE release was obtained at 10⁻¹¹M TRH and the highest release of 15 HETE was at 10⁻⁹ M TRH. PRL secretion by GH₃ cells challenged by TRH showed the same pattern as 15 HETE release, and the correlation between PRL and 15 HETE was significant (p <0.001).

These data indicate that 15 HETE is the lipoxygenase metabolite released in the largest amounts by GH₃ cells and suggest some physiological interaction between 15 HETE and TRH in the control of PRL secretion.

This study was designed to compare prostaglandin (PG)-synthesizing activity in rat small intestinal microsomes in the lst, 3rd, and 6th weeks of life and at maturity (>100 days). When an incubation system was used containing 2 mg microsomal protein, 0.5 mM (−)-epinephrine and 1 mM reduced glutathione, the highest PG-synthesizing activity was achieved by incubating 0.157 mM 1-¹⁴C-arachidonate (specific activity 2.6 × 10⁶ dpm/μmol) at 37°C for 5 min. The labeled metabolites were extracted and then separated with high performance liquid chromatography. The four PGs analyzed were 6 keto-prostaglandin F₁α (6-keto-PGF_1α), thromboxane B₂, prostaglandin F_2α and prostaglandin E₂. Enzymatic activity for the synthesis of 6-keto-PGF_1α was much higher than that for the other PGs. A significant difference was observed for the bioconversion from arachidonate to 6-keto-PGF_1α and total PGs among the four age groups of rats. The postweanling groups (week 6 and adult) showed significantly higher enzymatic activities for the syntheses of 6-keto-PGF_1α and total PGs than did the preweanling groups (weeks 1 and 3).