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S Moncada

Publications and source records attributed to S Moncada.

At least 361 records · Page 20Linked to original sources
PubMed1985

The anti-inflammatory effect of glucocorticoid-induced phospholipase inhibitory proteins.

The anti-inflammatory effect of glucocorticoids has been investigated in two standard models of experimental inflammation, i.e. rat paw oedema induced by carrageenin or dextran. Both types of oedema are suppressed by dexamethasone while indomethacin and BW755C only suppress carrageenin oedema. Dexamethasone inhibits dextran oedema according to the accepted mode of action of steroid hormones since the inhibition occurs after a 2-3 h time lag and is abolished by pretreating animals with actinomycin D. Dextran oedema and carrageenin oedema are also controlled by endogenous corticoids since adrenalectomy potentiates the paw oedema formation induced by low concentrations of phlogogenic agents. It has been shown that glucocorticoids induce both in vitro and in vivo the formation and release of antiphospholipase proteins which are anti-inflammatory in that they greatly suppress carrageenin oedema. However, these proteins have no effect on dextran oedema. We conclude that the inhibition of dextran oedema by glucocorticoids depends on the formation of another type of anti-inflammatory protein.

Animals↗
PubMed1985

Evaluation of inhibitors of eicosanoid synthesis in leukocytes: possible pitfall of using the calcium ionophore A23187 to stimulate 5' lipoxygenase.

The effect on arachidonate metabolism of two compounds (BW755C and benoxaprofen) which have been reported to inhibit 5' lipoxygenase in leukocytes has been evaluated in human polymorphonuclear leukocytes (PMN) stimulated with the calcium ionophore A23187 and serum-treated zymosan (STZ). The syntheses of leukotriene B4 (LTB4) and thromboxane B2 (TXB2) from endogenous substrate were determined by specific radioimmunoassays as indicators of 5' lipoxygenase and cyclo-oxygenase activity in the PMN respectively. Benoxaprofen inhibited the synthesis of leukotriene B4 by human PMN stimulated with the calcium ionophore A23187, but it was approximately 5 times less potent than BW755C. However, benoxaprofen (IC50 1.6 X 10(-4)M) was approximately 100 times less potent than BW755C (IC50 1.7 X 10(-6)M) at inhibiting leukotriene B4 synthesis induced by serum-treated zymosan. Both drugs inhibited thromboxane synthesis by leukocytes stimulated with A23187 or serum-treated zymosan at similar concentrations (approximately 5 X 10(-6)M). The data obtained using STZ as stimulus are consistent with previous in vivo studies and indicate that benoxaprofen is a relatively selective inhibitor of cyclo-oxygenase. However, this selectivity was far less apparent when A23187 was used as a stimulus to release the eicosanoids which suggests that this inhibition could be via an indirect mechanism and therefore A23187 should be used with caution as a stimulus of 5' lipoxygenase for evaluating inhibitors of eicosanoid synthesis.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1985

An ultrastructural study of stored human platelets after washing using prostacyclin.

The morphology of washed human platelets stored at 4 degrees C has been examined over a period of 96 h. Platelets prepared using prostacyclin showed good preservation of their internal structure. These platelets showed no signs of activation when stirred in an aggregometer and only small reversible aggregates were formed during storage. In contrast, platelets prepared using a more conventional method, which does not use prostacyclin, showed poor preservation of internal structure. Storage and stirring of these platelets resulted in activation and morphological deterioration. These observations support our previous finding that prostacyclin prolongs the viability of washed human platelets in vitro.

Blood Platelets↗
PubMed1985

Differential release of eicosanoids by bradykinin, arachidonic acid and calcium ionophore A23187 in guinea-pig isolated perfused lung.

The effects of infusions of bradykinin (0.2 microM), calcium ionophore A23187 (0.5 microM) and arachidonic acid (13 microM) on the release of eicosanoids from the guinea-pig isolated perfused lung were investigated using radioimmunoassay for thromboxane B2 (TXB2), 6-oxo-prostaglandin F1 alpha (6-oxo-PGF1 alpha), PGE2, leukotriene B4 (LTB4) and LTC4 and bioassay using the superfusion cascade. Bradykinin released more 6-oxo-PGF1 alpha than TXB2, whereas arachidonic acid and ionophore released more TXB2 than 6-oxo-PGF1 alpha. The time course of eicosanoid release varied with the stimulus: bradykinin and arachidonic acid produced an immediate release, whereas the ionophore showed a slower onset of release. Although the amounts of LTB4 and LTC4 released by the ionophore were very low according to radioimmunoassays, there was evidence from the bioassay of release of a leukotriene-like substance, thought to be LTD4. The leukotriene antagonist FPL 55712 lacks specificity in the guinea-pig trachea; at the concentration used (2 microM) it antagonized contractions of the tracheal strip to PGE2 as well as to LTC4. Our results show that in the guinea-pig perfused lung the metabolism of exogenous arachidonic acid is both qualitatively and quantitatively different from the metabolism of endogenous arachidonic acid; furthermore, the profile of eicosanoid production is stimulus-dependent.

6-Ketoprostaglandin F1 alpha↗
PubMed1984

Prostacyclin-sensitive adenylate cyclase in cultured myocytes: differences between rabbit aorta and mesenteric artery.

Prostacyclin relaxes isolated strips of rabbit mesenteric artery and stimulates cholesteryl ester hydrolysis in rabbit aortic smooth muscle cells. Both effects are considered to be mediated by an increase in intracellular cAMP levels. Here we report that prostacyclin, prostaglandin E1 and two stable analogues of prostacyclin (5,6-dihydroprostacyclin and carbacyclin) dose dependently stimulate adenylate cyclase activity in membranes of cultured myocytes from both rabbit aorta and mesenteric artery. The rank order of potency in both systems was prostacyclin greater than carbacyclin greater than prostaglandin E1 greater than 5,6-dihydroprostacyclin, which parallels the order of potency observed for the vasodilator actions. Three other prostanoids, with limited vasoactive properties, prostaglandin D2, BW245C and 6-keto-prostaglandin F1 alpha failed to stimulate significantly adenylate cyclase activity. The two cell types differ in that the enzyme activation in aortic cell involves the interaction of each prostaglandin with one component of the adenylate cyclase system, while in mesenteric arterial cells the activation is brought about by the interaction with a higher and a lower affinity class of components.

Adenylyl Cyclases↗
PubMed1984

Effect of orally administered eicosapentaenoic acid (EPA) on the formation of leukotriene B4 and leukotriene B5 by rat leukocytes.

Eicosapentaenoic acid (EPA) is a poor substrate for the fatty acid cyclo-oxygenase but is a good substrate for lipoxygenase enzymes which catalyse the biosynthesis of hydroperoxy-acids, hydroxy-acids and leukotrienes. Recently, we reported that leukotriene B5 (LTB5) was at least 30 times less potent than LTB4 in causing aggregation, chemokinesis and degranulation of polymorphonuclear leukocytes in vitro. In this paper, the effect of oral administration of EPA on LTB4 and LTB5 production by rat leukocytes stimulated with the calcium ionophore, A23187, was assessed. The concentration of LTB was determined by radioimmunoassay and also by reverse-phase high pressure liquid chromatography using PGB3 as internal standard. Supplementation of a normal rat diet with EPA (240 mg/kg per day) for 4 weeks caused a significant increase in the formation of LTB5 and a decrease in the synthesis of LTB4 by stimulated leukocytes. The EPA-rich diet significantly increased the EPA content of leukocyte phospholipids without altering the content of arachidonic acid (AA) or linoleic acid. The ratio of EPA/AA in leukocytes correlated (r = 0.795, P less than 0.001) with the LTB5/LTB4 ratio produced after stimulation of leukocytes. If LTB4 has a chemotactic role during inflammation, the present data suggest that an EPA rich diet could decrease the accumulation of leukocytes at sites of inflammation.

Administration, Oral↗
PubMed1984

Prostacyclin modulates the responses to leukotrienes C4 and D4 of guinea-pig airway smooth muscle.

Superfusion of lung parenchymal strips or tracheal strips from the guinea-pig with effluent from perfused isolated lungs reduced the contractions elicited by leukotriene C4 (LTC4) and leukotriene D4 (LTD4) but not those elicited by acetylcholine (ACh). Incubation of the lung perfusate for 15 min at 37 degrees C removed the inhibitory effect, as did treatment of the lungs with indomethacin (0.5 microgram ml-1) suggesting that a labile cyclo-oxygenase product was causing the inhibition. Addition of prostacyclin (0.8-5.0 ng ml-1) to the fluid superfusing tracheal and parenchymal strips produced a dose-related decrease in leukotriene-induced contractions, whereas 6-oxo-PGF1 alpha and PGE2 were inactive. Contractions of tracheal strips induced by LTC4 were significantly enhanced by infusion of PGF2 alpha. Parenchymal strips usually developed tachyphylaxis to repeated doses of LTC4. This tachyphylaxis has less evident in the presence of indomethacin (2 micrograms ml-1). Contractions of parenchymal and tracheal strips to histamine, acetylcholine and the stable thromboxane mimetic U-46619 were unaffected by infusion of prostacyclin (5 ng ml-1). These results indicate that prostacyclin selectively antagonises airway smooth muscle reactivity to LTC4 and LTD4 by a mechanism which remains to be elucidated.

Acetylcholine↗
PubMed1984

Biosynthesis and biological activity of leukotriene B5.

Several studies indicate that increased intake of eicosapentaenoic acid (EPA) in the diet may lead to decreased incidence of thrombotic events. Most investigators agree that this is achieved by competitively inhibiting the conversion of arachidonic acid (AA) to thromboxane A2 in the platelets. The effect of high EPA-intake on the formation of prostacyclin is less clear. However, EPA is a good substrate for lipoxygenase enzymes which results in formation of hydroperoxy- and hydroxy-acids, and, in some cases, leukotrienes. The biological activities of the leukotrienes derived from arachidonic acid suggest that they mediate or modulate some symptoms associated with inflammatory and hypersensitivity reactions. In order to clarify the possible effect of dietary manipulation on inflammatory processes, leukotriene B5 (LTB5) was prepared and its biological activities assessed. LTB5 was biosynthesized by incubation EPA with glycogen-elicited polymorphonuclear neutrophils (PMN) from rabbits in the presence of the divalent cation ionophore, A23187. The LTB5 was extracted from the incubate using mini-reverse phase extraction columns (Sep-pak) and purified by reverse-phase high pressure liquid chromatography (RP-HPLC). The purity of the product assessed by repeat RP-HPLC and straight phase (SP) HPLC was greater than 95%. Ultra-violet spectrophotometry of the product confirmed its purity and also provided assessment of the yield. The biological activity of LTB5 was assessed and compared with that of LTB4 in the following tests: aggregation of rat neutrophils, chemokinesis of human PMN, lysosomal enzyme release from human PMN and potentiation of bradykinin-induced plasma exudation. In all these tests, LTB5 was considerably less active (at least 30 times) than LTB4.

Animals↗