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The role of PAF (platelet-activating factor) in early pregnancy has been recently postulated. Indeed, platelet count is markedly reduced immediately prior to and returns to normal following ovoimplantation. Using a pharmacological approach, we therefore further investigated the possible involvement of PAF in ovoimplantation. BN 52021 (10 nmol), a PAF antagonist, was administered after fecondation in the lumen of the left uterine horn. A group of animals was injected with the vehicle alone. The animals were sacrificed 1 week latter and the number of implanted embryos in the treated horn and in the untreated contralateral one was assessed. When injected on day 4 of pregnancy, the PAF antagonist, BN 52021, inhibited in a dose-dependent fashion ovoimplantation suggesting a role for this lipid mediator in this process. Total inhibition of ovoimplantation was observed in the horns treated with indomethacin, NDGA or BW 755 C. In addition, a significant inhibition of ovoimplantation was also produced by the lipoxygenase inhibitor, EP 10045 (10nmol). Since both PAF and leukotrienes trigger the generation of prostaglandins in various tissues, our results indicate that these two lipid mediators may be implicated in early stages of the inflammatory reaction accompanying ovoimplantation and may contribute to the local generation of cyclooxygenase metabolites.

The effects of BN 52021, a new specific paf-acether receptor antagonist and the total Ginkgo Biloba extract (GBE 761) from which this product was isolated, were studied in the rat on paf-acether-induced permeability and cell number changes and on endotoxin-induced lethality. Their activities were compared to those of cyclooxygenase, 5-lipoxygenase and phospholipase A2 inhibitors. BN 52021 given s.c. or orally exerted a dose-related inhibition of paf-acether deleterious effects as well as of endotoxin lethality whereas the other drugs tested were poorly effective. These results strongly suggest paf-acether involvement in endotoxic and septic shock.

Endotoxemia and gram negative sepsis remain a clinically important problem since mortality rate is still high in these diseases. Recently, the participation of some new potential mediators in this pathology is beginning to be demonstrated but the results obtained on animal models with specific inhibitors are contradictory. In order to clarify the pathological importance of icosanoids and PAF-acether in the septicemic process, we investigated the effects of indomethacin (IND) a cyclooxygenase inhibitor, NDGA and EP 10045 two lipoxygenase inhibitors, dexamethasone (DXM) a phospholipase A 2 inhibitor and BN 52021 a PAF-acether receptor antagonist, on the Salmonella enteritidis-induced endotoxic shock (E.S.) in the rat. Injected subcutaneously 15 min before the test, NDGA, EP 10045 and IND were moderately effective when DXM completely prevented the endotoxin lethality. BN 52021 decreased the death rate in a dose-related manner and exerted at a non-active dose a synergistic effect on IND treatment. Furthermore, given orally 1 hour before endotoxin, it provided a potent protective effet. Our results seem to confirm that PAF-acether exerted alone, or in conjunction with products of the cyclooxygenase pathway, a key role in E.S. when LTs seem to play a role of minor importance.

Oedema is one of the major complication of cerebral ischaemia being at the same time a consequence and an aggravating factor.Its firstphase is intracellular and cytotoxic, with breakdown of ionic pumps through loss of energy, resulting in a whole sequence of ionic pertubations characterized by loss of intracellular K+ and accumulation of water and Na+, Cl−, and Ca2+ ions in the cells of the ischaemic zone.

Platelet-activating factor (PAF) has recently been shown to be a potent ulcerogenic agent in the stomach and intestinal mucosa. Its extract mechanism of action is not yet known although histological studies suggest that vasocongestion is an important feature of PAF-induced damage. We have therefore studied the activity of various agents with different modes of action toward PAF-induced gastrointestinal lesions in the rat (PAF 2 micrograms/kg i.v.; macroscopic lesions of tissue scored 20 min later; arbitrary scale from 0 to 4). Drugs were administered either i.m., s.c. (5 min) or orally (30 min) before PAF injection. PAF-induced gastric lesions were strongly inhibited by the natural PAF-antagonist BN 52021 as well as by atropine sulphate and cimetidine which implicates cholinergic stimulation in the ulcerogenic activity of PAF. The somatostatin analog BIM 23014 was also very potent against PAF, perhaps by reducing the parasympathetic stimulation in the gastric wall as described for somatostatin. Allopurinol, which is a free radical scavenger also almost totally inhibited PAF-induced gastric damage, suggesting that neutrophils are involved in the mucosal lesions. The considerable inhibition of the gastric effects of PAF found in neutrophil-depleted animal supports this hypothesis. Theophylline and disodium cromoglycate, mast cell stabilizing drugs which were also active in our model, could act by protecting mast cell degranulation induced by free radicals released from activated neutrophils. A multifunctional process seems to determine the mucosal gastric damage induced by PAF, but parasympathetic stimulation and neutrophil activation play a major role in this pathology.