The Effect of Inhibitors of Arachidonic Acid Metabolism on Drug‐induced Contractions in Isolated Tracheal Smooth Muscle of the Pig

Abstract

The regulation of drug‐induced tone in airways smooth muscle was examined in an isolated preparation of swine tracheal smooth muscle. The trachea contracted (isometric) to histamine, 2‐pyridylethylamine (2‐PEA), acetylcholine and K+ but no responses to histamine H2‐receptor agonists were observed. Histamine‐induced contractions (100 μm) were potentiated by 213.3% by indomethacin (1 μm) and by 126.9% by sodium salicylate (250 μm). These inhibitors had only slight or no effects on acetylcholine‐induced tone. 2‐PEA responses were also potentiated by indomethacin but there were no changes in the response to H2‐receptor agonists in the presence of indomethacin. The indomethacin‐mediated potentiation of histamine was blocked by 5, 8, 11, 14‐eicosatetraynoic acid (10 μm). FPL 55712 had no effect on these responses. Mepacrine (100 μm) inhibited responses to histamine but not those to acetylcholine. No effect was observed with dexamethasone (up to 100 μm). Prostaglandin E2 caused relaxation but arachidonic acid did not. The possibility that histamine H1‐agonist‐induced contractions are regulated by contractile products of the arachidonic acid lipoxygenase pathway is discussed.

EFFECT OF ETYA AND BW 755c ON ARACHIDONATE‐INDUCED CONTRACTIONS IN THE GUINEA‐PIG ISOLATED TRACHEA

“…A clear relationship has been established between 'aspirin-induced asthma' and inhibition of prostaglandin production (see Szczeklik, Gryglewski & Czerniawska-Mysik, 1977). However, the present results and those reported elsewhere (Adcock & Garland, 1980;Mitchell, 1982) show the need for further experimentation on the possible involvement of arachidonic acid lipoxygenase products in the regulation of airways smooth muscle and 'aspirin-induced asthma'.…”

Pharmacological studies into cyclo‐oxygenase, lipoxygenase and phospholipase in smooth muscle contraction in the isolated trachea

“…This occurred whether tissues were preincubated in mepacrine or whether mepacrine was administered later on during a muscle contraction. Mitchell, 1982a) suggesting that non-specific toxic effects of mepacrine are not involved in its effect on the histamine response. These observations further reinforce the suggestion that during the histamine-induced contraction (and in the presence of indomethacin) a lipoxygenase product(s) of arachidonate augments muscle contraction.…”

“…It was shown previously that indomethacin has little or no effect on contractions to acetylcholine in the pig trachea (Mitchell, 1982a). Indomethacin has been found to enhance drug-induced contractions of airways smooth muscle by numerous authors and it has been proposed that this effect is due to the removal of the influence of relaxant prostaglandins (e.g.…”

“…The methods used for recording isometric tension responses in pig isolated tracheae were the same as previously described (Mitchell, 1982a). Pig tracheae were obtained from local abattoirs; they were usually used fresh but in a few experiments they were first stored in Krebs solution at 4°C for 4-24 h. Tracheal strips were placed in organ baths, under a passive tension of 2 g. Experiments were begun once tissues were showing consistent responses to repeated challenges with a submaximal concentration of acetylcholine (>60 min).…”

“…of Physiology, University of Western Australia, Nedlands 6009, Australia. pig isolated trachea it was shown that mepacrine inhibits contractions to histamine but not those to acetylcholine (Mitchell, 1982a) from which the involvement of arachidonate metabolites in druginduced muscle contractions might be inferred. It has been noted, however, that anti-lipoxygenase and cyclo-oxygenase drugs do not inhibit histamine contractions but this was in the guinea-pig trachea (Adcock & Garland, 1980;Burka & Paterson, 1980;Hitchcock & Kokolis, 1981).…”