Effects of Modulators of Arachidonic Acid Metabolism on the Synthesis and Release of Slow‐reacting Substance of Anaphylaxis

Abstract

Slow‐reacting substance of anaphylaxis (SRS‐A) was released in the peritoneum of passively sensitized rats challenged with ovalbumin and from rat isolated peritoneal cells stimulated with calcium ionophore A23187. Both monocytes (macrophages) and mast cells appear to be involved in the synthesis and release of SRS‐A. The immunological release of SRS‐A in vivo is enhanced by indomethacin and inhibited by dexamethasone, mepacrine, 1‐phenyl‐3‐pyrazolidone (1‐P‐3‐P), and methylimidazole. SRS‐A release induced by A23187 in vitro is inhibited by dexamethasone, indomethacin, 1‐P‐3‐P, eicosatetraynoic acid (ETA) and 15‐hydroperoxy arachidonic acid. The inhibition induced by dexamethasone, indomethacin and 1‐P‐3‐P is reduced by an increase in the calcium concentration from 1 mm to 5 mm, whereas the inhibition induced by ETA is increased. The results suggest that a lipoxygenase is important in the synthesis and release by SRS‐A.

Histamine and leukotriene‐independent guinea‐pig anaphylactic shock unaccounted for by Paf‐acether

“…Assays were performed in the presence of mepyramine and indomethacin, in order to rule out the role of histamine and cyclo-oxygenase products respectively. Neither BW755c nor ETYA, at concentrations which block the lipoxygenases (Hitchcock, 1978;Burka & Flower, 1979;Orning & Hammarstrom, 1980;Armour et al, 1981;Piper & Temple, 1981;Pattersson et al, 1981) inhibited the effects of Paf-acether. Moreover, BW755c suppressed the generation of leukotriene-like (i.e., FPL 55712 -inhibitable) substances detected with the coupled strips, validating its use as an inhibitor of the formation of leukotrienes in our system.…”

On the Preparation of Highly Purified Slow Reacting Substance of Anaphylaxis (Srs‐a) From Biological Extracts

“…Thus the conclusion of the first group, that SRS-A is a cyclo-oxygenase metabolite, differs from that of the second group who concluded that SRS-A is a metabolite of the lipoxygenase pathway. We have recently shown the situation to be even more complicated (Burka & Flower, 1979), in that SRS-A generated in vivo is enhanced by indomethacin but blocked by phenidone, an inhibitor of both cyclo-oxygenase and lipoxygenase pathways (Blackwell & Flower, 1978).…”

“…Crude rat SRS-A was generated either by antigen challenge in vivo (Orange, Valentine & Austen, 1968) or by the calcium ionophore technique in vitro (Bach & Brashler, 1974;Burka & Flower, 1979). When the material was not processed immediately, it was stored in buffer aqueous solutions at -20°C.…”

Mediators of arachidonic acid‐induced contractions of indomethacin‐treated guinea‐pig airways: leukotrienes C4 and D4

“…It has been assumed that leukotriene biosynthesis is dependent on membrane events which activate phospholipase A2 such that free AA is made available to the metabolic enzymes (Burka & Flower, 1979). The initial membrane events such as calcium mobilization also appear to be necessary for activation of the lipoxygenase pathway (Borgeat & Samuelsson, 1979;Jakschik & Lee, 1980).…”