Cyclo‐oxygenase inhibitors antagonize indirectly evoked contractions of the guinea‐pig isolated ileum by inhibiting acetylcholine release

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Abstract
1 The effects of indomethacin, sodium meclofenamate and ketoprofen on the contractile responses of the guinea-pig isolated ileum to directly and indirectly evoked stimuli were investigated. The effects of the cyclo-oxygenase inhibitors on acetylcholine (ACh) release from plexus containing longitudinal muscle strips were also studied. 2 The cyclo-oxygenase inhibitors reduced contractile responses to transmural stimulation (TMS) and nicotine at concentrations which had no effect on ACh-induced contractions. 3 In whole ileum preparations (WIP) indomethacin and ketoprofen (40 μg ml−1) reduced TMS responses by 17 ± 1.8% and 12 ± 1.8% (n = 6), respectively (30 min incubation). In longitudinal muscle strips (LMS) in which Auerbach's plexus is exposed, indomethacin and ketoprofen (1 μg ml−1) reduced TMS responses by 28 ± 2.3% and 34 ± 2.7% (n = 6), respectively (10 min incubation). Thus the cyclo-oxygenase inhibitors were up to 80 times more effective in LMS than in WIP. The drugs were similarly more effective in blocking nicotine contractions in LMS than in WIP. 4 The cyclo-oxygenase inhibitors reduced basal and stimulated ACh release from LMS. For example, indomethacin (1 μg ml−1) reduced stimulated ACh release by 35% after 10 min incubation. The percentage inhibition increased to 79% after 40 min incubation (n = 6). 5 Prostaglandin E2 (PGE2) (0.1–2.5 ng ml−1) restored the contractile responses and ACh release depressed by the cyclo-oxygenase inhibitors but not the contractile responses depressed by atropine. PGF2α had no effect on mechanical responses or ACh release depressed by the cyclo-oxygenase inhibitors. 6 It is concluded that the cyclo-oxygenase inhibitors studied reduced responses to transmural stimulation and nicotine by inhibiting ACh release. The site of action is the postganglionic parasympathetic nerve. 7 It is suggested that the reason why previous investigators needed to use high doses of cyclo-oxygenase inhibitor in the ileum is because the action of the inhibitor is limited by diffusion barriers. There was no evidence to support the view that there is more than one pool of cyclo-oxygenase in guinea-pig gut.