ABSTRACT
Fenflumizole (2-(2,4-difluorophenyl)-4,5-bis(4-methoxyphenyl)imidazole), a new non-steroidal anti-inflammatory agent, was investigated for interference with cyclo-oxygenase activity in vivo, ex vivo and in vitro in comparison with indomethacin (and aspirin). Fenflumizole was comparable to indomethacin ex vivo in inhibition of thromboxane (TX)A2 production in rabbit platelets and inhibition of prostaglandin (PG)I2 (approximately prostacyclin) generation in rabbit mesenteric arteries and in vivo as an inhibitor of PGE2 formation in inflammatory exudates in rats. Fenflumizole was 18 times less active than indomethacin in inhibition of PGE2 synthesis in vitro and 170 times weaker as an inhibitor of PGI2 generation in the rat stomach mucosa ex vivo. Fenflumizole was 20-50 times more potent than indomethacin in vivo in inhibition of arachidonic acid induced bronchoconstriction in guinea-pigs, in inhibition of platelet aggregation on tendons superfused with blood from rabbits and in vitro in inhibition of aggregation of human and rabbit platelets. Neither fenflumizole nor indomethacin inhibited TXA2-synthetase in vitro. Aspirin-when tested-was less potent than fenflumizole and indomethacin. It is concluded that fenflumizole is a potent cyclo-oxygenase inhibitor. The very potent activity of fenflumizole against platelet aggregation and bronchoconstriction suggests a selectivity in the mode of action. The weak inhibition of gastric PGI2 generation may account for the previously observed weak gastro-ulcerogenicity of fenflumizole.
Subject(s)
Arachidonic Acids/pharmacology , Cyclooxygenase Inhibitors , Imidazoles/pharmacology , Animals , Aspirin/pharmacology , Blood Platelets/metabolism , Cattle , Dinoprostone , Drug Interactions , Epoprostenol/biosynthesis , Exudates and Transudates/metabolism , Guinea Pigs , In Vitro Techniques , Indomethacin/pharmacology , Inflammation/metabolism , Male , Platelet Aggregation/drug effects , Prostaglandins E/biosynthesis , Rabbits , Rats , Rats, Inbred Strains , Thromboxane A2/biosynthesisABSTRACT
Prostaglandins E2 and F2 alpha and arachidonic acid were injected into various brain structures outside the hypothalamus in rats. The body temperature rise induced by PGE2, but not by PGF2 alpha or arachidonic acid, was probably due to its diffusion or transport into the hypothalamus. Comparison of the latencies of the hyperthermic response to PGE2, PGF2 alpha, and arachidonic acid revealed that PGE2 was the most rapidly acting agent in structures located close to the hypothalamus. In contrast, arachidonic acid acted most rapidly after administration into the nucleus reticularis pontis caudalis.
Subject(s)
Arachidonic Acids/pharmacology , Body Temperature/drug effects , Prostaglandins E/pharmacology , Prostaglandins F/pharmacology , Animals , Arachidonic Acid , Dinoprost , Dinoprostone , Endotoxins/pharmacology , Escherichia coli , Hypothalamus , Injections , Male , Rats , Rats, Inbred Strains , Time FactorsSubject(s)
Lung/drug effects , Muscle Contraction/drug effects , Thromboxane A2/pharmacology , Thromboxanes/pharmacology , Animals , Aorta/drug effects , Arachidonic Acids/metabolism , Arachidonic Acids/pharmacology , Autacoids/pharmacology , Dose-Response Relationship, Drug , Female , Guinea Pigs , Horses , Male , Microsomes , Platelet Aggregation , Prostaglandins H , Rabbits , Thromboxane A2/biosynthesisABSTRACT
In vivo anti-platelet de-aggregatory activity of exogenous prostacyclin is enhanced after its passage through the pulmonary circulation of anaesthetized cats, probably because of a concomitant generation of endogenous prostacyclin by the lungs. Evidence is also presented that perfused lungs of guinea pigs and rats spontaneously release considerable amounts of prostacyclin. It is therefore postulated that a continuous biosynthesis of prostacyclin by pulmonary endothelium is a general physiological phenomenon, while the generation of thromboxane A2 by lungs occurs in response to pathological stimuli. Coronary and cerebral arteries are supposed to benefit from this hormonal function of the lungs.
Subject(s)
Epoprostenol/biosynthesis , Lung/metabolism , Prostaglandins/biosynthesis , Animals , Arachidonic Acids/metabolism , Aspirin/pharmacology , Cats , Epoprostenol/blood , Guinea Pigs , Lung/drug effects , Male , Platelet Aggregation/drug effects , Positive-Pressure Respiration , Rats , Thromboxane A2/metabolismABSTRACT
The aim of the present study was to investigate the possibility that endotoxin fever in rats is mediated by arachidonic acid (AA) which in turn is converted to the active metabolites such as prostaglandin (PG) E2, PGF2alpha, thromboxane A2 (TxA2), or prostacyclin (PGI2). Evidence is presented indicating that PGE2 induces fever (not hyperthermia) by acting on the anterior hypothalamic preoptic area. Conversely, both PGF2alpha and AA produce mutually similar hyperthermia and there is no correlation between their microinjection sites in the diencephalon and the observed hyperthermic response. In addition, evidence is presented suggesting that involvement of other metabolites of AA, namely TxA2 and PGI2 in the mediation of endotoxin fever in rats seems unlikely. Only PGE2-induced fever is significantly similar, consistent with the parameters of this study, to endotoxin-induced fever in rats. AA-induced hyperthermia is probably brought about by increased levels of PGF2alpha or both PGF2alpha and PGE2 in the hypothalamus following AA injection. It seems highly unlikely that endotoxin produces fever in rats through the increased availability of free AA or through the activation of the PG endoperoxide synthetase in the hypothalamus. The mechanism by which endotoxin may increase PGF2 levels in the rat hypothalamus remains unknown.
