Importance of secondary TXA2 release in mediating of endothelin-1 induced bronchoconstriction and vasopressin in the guinea-pig.

The i.v. bolus application of 1 nmol/kg endothelin-1 (ET-1) in anaesthetized and ventilated guinea-pigs caused an increase in mean arterial blood pressure (BP) and a bronchoconstriction. Both have been reduced or abolished by COX inhibition (ASA) or substances specifically reducing the thromboxane A2 (TXA2) generation (HOE 944) or receptor binding (BM 13177). The significant increase in TXB2 concentrations in plasma and bronchoalveolar lavage (BAL) after ET-1 challenge (15-fold and 4-fold, respectively) have been reduced or abolished by ASA as well as HOE 944 and not altered by BM 13177.

PAF-induced death in NMRI mice--a suitable shock model for testing new PAF receptor antagonists. Correlation with eicosanoid related substances.

The effects of PAF antagonists, of substances which influence the arachidonic acid metabolism, and of dexamethasone and ketotifen were evaluated in an acute PAF-induced mortality model in female NMRI mice. We established a dependence of sensitivity to PAF on strain (AB mice showed no dose dependence) and on sex of the animals as well as on the PAF charges used in our experiments. PAF produced resistance in surviving animals against the PAF-induced death on repeated application. The PAF antagonists, WEB 2170 and WEB 2086, provided the best dose-dependent protection against PAF toxicity, followed by dexamethasone, by the COX/LOX synthetase inhibitor X 86 (a BW 755 C-analogue) and by the PAF receptor antagonist BN 52021. Particularly remarkable was the excellent prevention by aspirin. Aspirin may not only inhibit the cyclooxygenase pathway but also endogenous PAF synthesis. Other drugs, i.e. indomethacin, the thromboxane receptor antagonist, BM 13177, the thromboxane synthetase inhibitor, HOE 944, as well as the lipoxygenase inhibitors (NDGA, esculetin, SHAM and phenidone) exerted a dose-dependent protection only at high doses.

Influence of aminophylline and ketotifen in comparison to the lipoxygenase inhibitors NDGA and esculetin and the PAF antagonists WEB 2170 [correction of 2107] and BN 52021 on endothelin-1 induced vaso- and bronchoconstriction.

Theophylline (p less than 0.05) and ketotifen (p greater than 0.05) markedly reduced, but the lipoxygenase inhibitors and PAF receptor antagonists were without any influence on the endothelin-1 (ET-1 1 nmol/kg i.v.) induced increase of pulmonary inflation pressure of anaesthetised and ventilated guinea-pigs. The ET-1 induced increase in mean arterial blood pressure as well as the secondary TXB2 release into bronchoalveolar lavage fluid or plasma was not decreased. TXB2 release cannot be the only mechanism of bronchopulmonary ET-1 effects in guinea-pigs in vivo.

Influence of iloprost and various prostaglandin derivatives on mouse skin allograft survival, HLA-DR antigen expression and eicosanoid metabolism by human leukocytes.

Treatment of mice bearing allogeneic tail skin grafts with iloprost, a stabilized prostacyclin derivative, as well as dexamethasone prolonged graft survival. Nalador and flunoprost, stabilized prostaglandin E analogues, had similar but weaker effects. The thromboxane agonist U 46619 had no effect on graft rejection. An incubation of human monocytes with iloprost or prostaglandin E2 led to a dose-dependent reduction of HLA-DR antigen expression by these cells. Furthermore, a suppressive effect of these prostaglandin derivatives on the calcium ionophore stimulated release of arachidonic acid metabolites by human polymorphonuclear leukocytes has been shown, which demonstrates an antiinflammatory action of these drugs. Additionally, the eicosanoids were determined in the tail skin after complete allograft rejection. The importance of thromboxane for the rejection of skin grafts has not been confirmed. These data, along with the known antiaggregatory and antiischemic cytoprotective effects of iloprost, suggest that this newly developed drug may be all the more important in clinical organ transplantation.

[Modification of lipoxygenase products in bone by the linoleic acid content of the diet]. / Beeinflussung von Lipoxygenaseprodukten im Knochen durch den Linolsäuregehalt der Nahrung.

Eicosanoids are supposed to participate in the regulation of bone metabolism. 30 male white rats of the wistar strain were fed on a diet rich in linoleic acid (LA), on a diet poor in LA and on a pellet diet after 3 month up to an age of 5 month. The formation of leukotrienes (LT) C4, D4, and E4 from the proximal tibia metaphysis after LA rich diet has been compared to the formation from LA poor and pellet diet. LA rich diet increased the formation of LTC4, D4 and E4 in the proximal tibia metaphysis. The properties of eicosanoids as local mediators in the bone were discussed.

Influence of the PG-analogues iloprost, nalador and nileprost on rejection time and TXB2 content of murine tail skin allografts.

Iloprost (2 X 330 micrograms/kg sc./d) better than nalador (2 X 500 micrograms/kg sc./d) prolonged the average time until the complete rejection of murine tail skin allografts in inbred mice. Nileprost (2 X 500 micrograms/kg sc./d) showed a similar trend. The TXB2 content in the ambient skin at the transplantation site was significantly diminished by all three PG-analogues, but by nileprost more than by iloprost or nalador.

Inhibition of lipoxygenase (LOX) or of cyclooxygenase (COX) improves survival of rats in endotoxin shock.

In a well defined endotoxin (ET) shock model we compared the influence of a selective LOX-inhibitor FLM 5011 and the COX-inhibitor Acetylsalicylic acid (ASA) on survival as well as on their effects on TXB2 and 6-oxo-PGF1 and on selected parameters characterizing the shock syndrome. Pretreatment with both substances reduced the lethality rate. Neither TXB2 nor the PGF1 concentration revealed a consistent trend after therapeutic intervention. None of the investigated mediators could be identified as the primary "shock mediator".

Influence of inhibitors of the eicosanoid metabolism, of antagonists of the eicosanoids and of PAF on mortality assayed in three biochemically characterized shock models.

Experiments were carried out to lower the mortality (LD70-90) of rats in ovalbumin-induced anaphylactic (DA) shock and in endotoxin-induced (ET) shock, and of mice after injection of Platelet-activating Factor (PAF shock) comparing the effects of the cyclooxygenase (COX)-inhibitors aspirin (ASA), indomethacin, of the COX-/lipoxygenase (LOX)-inhibitors nordihydroguajaretic acid (NDGA), phenidone and X 86 (analogue of BW 755c), of the inhibitor of thromboxane (TX) synthesis HOE 944, of the TX-antagonist BM 13177, of the PAF-antagonist BN 52021 and of ketotifen. Ketotifen was strongly effective in DA shock, COX- and LOX-inhibitors only slightly. Combined COX- and LOX-inhibitors and BN 52021 showed good effects in the ET shock. Ketotifen was inefficacious. All the used substances influenced the PAF shock. The shock syndromes were biochemically characterized by determination of isocitratedehydrogenase (ICDH) activity, lactate, glucose, haematocrit, numbers of thrombocytes and leucocytes, TXB2 and 6-keto-Prostaglandin(PG)F1 alpha.