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Saturated fatty acids (C10, C12, C14, C16 and C18) as well as lauryl sulphate inhibit the microsomal prostaglandin synthetase of bovine seminal vesicles (BSVM). The most potent inhibitors are lauryl sulphate, lauric and myristic acids ( ic 50 = 250 μ M ). The last two acids are strong ligands to hydrophobic sites of albumin. Indomethacin is also strongly bound to the hydrophobic sites of albumin; however, indomethacin inhibits the generation of prostaglandins at a concentration approximately 2500 times lower than the most active fatty acid inhibitor. The inhibitory action of fatty acids and indomethacin on prostaglandin synthetase activity has been measured by estimation of either PGE2 or malondialdehyde, which are generated from arachidonic acid by BSVM. The former procedure is more reliable and reproducible than the latter.

SummaryUsing our in vivo model for studying drugs which prevent deposition of thrombi or dissipate thrombi formed in extracorporeal circulation over a collagen strip superfused with arterial blood of anaesthetized and heparinized cats, we have found that dazoxiben - a thromboxane synthetase inhibitor - possesses not only antithrombotic but also thrombolytic potency in vivo (ED50 = 3.8 mg/kg i.v.). The thrombolytic potency of dazoxiben was antagonized by aspirin at a dose of 50 mg/kg i.v. Moreover, dazoxiben stimulated the generation of prostacyclin in isolated rat aortic slices incubated in platelet rich plasma, but not in platelet poor plasma. It is suggested that the thrombolytic potency of thromboxane synthetase inhibitors after their systemic administration is associated with the release of prostacyclin and/or prostacyclin-stable metabolites by the vascular endothelium owing to feeding of prostacyclin synthetase with prostaglandin endoperoxides acumulated in platelets following the inhibition of thromboxane synthetase.

Gastric mucosa of the rat generates both PGE2 and PGI2 activity in significantly higher concentrations in the antrum than in the fundus. Aspirin, given intravenously or intragastrically in doses producing gastric mucosal lesions, causes a dose-dependent decrease in the generation of mucosal PGE2 and PGI2, which is further enhanced by gastric perfusion of HCl. Exogenous PGE2 and PGI2 administered intravenously in doses not affecting gastric secretion almost completely prevented the formation of aspirin-induced ulcers. This study indicates that gastric mucosa is capable of generating PGE2 and PGI2 which may be responsible for its protection against chemical injury.

Summary When challenged with antigen fragments of mesentery of immunized guinea pigs released histamine and a prostaglandin-like substance (PGs). The release of both mediators was inhibited by hydrocortisone hemisuccinate (1.0–30.0 μg/ml) and dexamethasone (10.0 μg/ml). Indomethacin (10.0 μg/ml) and hydrocortisone hemisuccinate at low concentrations (0.05–0.6 μg/ml) suppressed the release of PGs, while the release of histamine was stimulated. It is suggested that glucocorticosteroids exert these effects due to their interaction with biomembranes.

Rat brain slices released spontaneously and after challenge with A23187 LTC4-like radioimmunoactivity. Total cat brain ischemia followed by short postischemic reperfusion period resulted in the increased release of lipid peroxides and PGE2 but not in LTC4-like substance by brain slices. In lumbar cerebrospinal fluid of patients with completed stroke presence of LTC4-like material was observed.

Intact platelets from atherosclerotic rabbits release more thromboxane B 2 (TXB 2 ) and 12-hydroxyeicosatetraenoic acid (HETE) than platelets from normal rabbits following incubation with [ l4 C]arachidonic acid (AA). In contrast, no difference is found between homogenates of platelets from normal and atherosclerotic animals. PGI 2 stimulates CAMP accumulation and inhibits TXB 2 formation more potently in intact platelets from atherosclerotic than from normal rabbits, but has no effect on AA metabolism in homogenised platelets.

The release of PGI2-like activity into the circulation in response to cholinergic agonists and modification of this response by beta-adrenergic antagonists was investigated in anaesthetized cats and healthy humans. Antiaggregatory activity in the arterial blood was continuously assayed by measuring platelet aggregation on blood superfused collagen strip. In some of the human experiments, after the administration of the drugs, the conversion of [14C]-arachidonate to [14C]-prostaglandins in the pulmonary vascular bed was studied. Cholinergic agonists stimulated the release of PGI2-like activity into the circulation, which effect was potentiated in cats by beta-adrenergic antagonists. In humans the latter agents did not stimulate the conversion of [14C]-arachidonate to prostaglandins in the pulmonary circulation and, moreover, inhibited the stimulatory cholinergic effect. The results suggest that an interplay between cholinergic and beta-adrenergic mediators may be involved, although in a different way in cats and in humans, in the release of PGI2-like activity into the systemic circulation.