leukotriene-b4 and ricinoleic-acid

A series of essential fatty acids and fatty acid derivatives were evaluated for their ability to inhibit [3H] leukotriene B4 (LTB4) binding to pig neutrophil membranes. The fatty acids varied in chain length, extent of unsaturation, position of unsaturation, and isomerization. Generally, fatty acids with two or more unsaturated sites and chain lengths of 18-22 were potent inhibitors of [3H]LTB4 binding; both n-3 and n-6 fatty acids were inhibitory. The most potent compounds tested were homogammalinolenic acid and ricinelaidic acid which gave Ki values of 1 microM and 2 microM in the binding assay. Ricinelaidic acid was also tested for its ability to inhibit LTB4-mediated chemotaxis (IC50 = 10 microM) and LTB4-induced calcium fluxes (IC50 = 7 microM) in isolated human neutrophils. Ricinelaidic acid did not show agonist activity in these assays. In an in vivo model of LTB4-induced bronchoconstriction, ricinelaidic acid and homogammalinolenic acid gave 46% and 53% inhibition, respectively, at a 1 mg/kg i.v. dose. These results indicate that essential fatty acids are LTB4 receptor antagonists, which may account in part for their reported anti-inflammatory activities.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Bronchoconstriction; Calcium; Cell Membrane; Chemotaxis, Leukocyte; Fatty Acids, Essential; Fatty Acids, Unsaturated; Humans; Leukotriene B4; Neutrophils; Receptors, Leukotriene B4; Ricinoleic Acids; Swine; Tritium

The seed oil of the plant Ixiolaena brevicompta is a rich source of crepenynic acid (octadec-cis-9-en-12-ynoic acid), which has been linked with extensive sheep mortalities in Western New South Wales and Queensland, Australia. A number of acetylenic fatty acids have been found to interfere with lipid and fatty acid metabolism and inhibit cyclooxygenase and lipoxygenase enzymes in a variety of tissues. We have investigated the effects of crepenynic acid and ximenynic acid (octadec-trans-11-en-9-ynoic acid) on leukotriene B4 and thromboxane B2 production in rat peritoneal leukocytes and compare them with non-acetylenic compounds linoleic and ricinoleic acids. In concentrations ranging from 10 to 100 microM linoleic acid and ricinoleic acid had only minimal effects on leukotriene B4 and thromboxane B2 production in ionophore-stimulated cells. Ximenynic acid gave dose-dependent inhibition of leukotriene B4, thromboxane B2 and 6-ketoprostaglandin F1 alpha production. Ximenynic acid appears to be a more effective inhibitor of leukotriene B4 than crepenynic acid with an IC50 of 60 microM compared to 85 microM. On the other hand, crepenynic acid is a much more effective inhibitor of the cyclooxygenase products, having an IC50 for thromboxane B2 of less than 10 microM. Both acetylenic fatty acids inhibited phospholipase activity in these cells by 40-50% at a concentration of 100 microM but had no inhibitory effect at 10 microM. These results indicate that crepenynic acid and ximenynic acid differentially inhibit the cyclooxygenase and lipoxygenase products of stimulated leukocytes, and that at high doses of these fatty acids the effect on these products may be partially due to inhibition of phospholipase A2.

Topics: Alkynes; Animals; Cyclooxygenase Inhibitors; Leukocytes; Leukotriene B4; Linoleic Acid; Linoleic Acids; Lipoxygenase Inhibitors; Oleic Acids; Peritoneal Cavity; Phospholipases; Rats; Ricinoleic Acids; Thromboxane B2

Rat isolated intestine incubated in Krebs solution converted exogenous [14C]-arachidonic acid into products that chromatographed with prostaglandins, leukotriene B4 and 5-hydroxy-eicosatetraenoic acid. Accumulation of these products was increased by the laxative ricinoleic acid (0.34 mM) or the calcium ionophore A23187 (7.6 microM). In the presence of the calcium antagonists TMB-8 (0.43 microM) or verapamil (0.2 microM) the mean effects of ricinoleic acid or the calcium ionophore were smaller. Stimulation of arachidonic acid metabolism by ricinoleic acid therefore seems likely to involve a calcium-dependent mechanism.

Topics: Animals; Arachidonic Acids; Calcimycin; Calcium; Colon; Fatty Acids, Unsaturated; Gallic Acid; Hydroxyeicosatetraenoic Acids; In Vitro Techniques; Leukotriene B4; Male; Prostaglandins; Rats; Ricinoleic Acids; Verapamil