STUDIES ON THE PROBABLE EFFECT OF PROSTAGLANDINS ON CHOLINERGIC TRANSMISSION IN ISOLATED GUINEA-PIG ILEUM.

Abstract

The effect of indomethacin, ketoprofen and sodium meclofenamate on contractions evoked by different stimuli in the guinea-pig ileum were investigated in Tyrode solution and in Krebs solution. The whole ileum preparation as well as the longitudinal muscle strip were used. In the whole ileum preparation, indomethacin (10 ugml⁻¹), sodium meclofenamate (5 ugm1⁻¹) and ketoprofen (10 ugml⁻¹) inhibited nicotine evoked but not transmural stimulation evoked or acetylcholine evoked contractions. In Krebs solution however, transmural stimulation evoked contractions were inhibited by the same concentration range of the Prostaglandin synthetase inhibitors. Inhibition of nicotine evoked contractions were more prominent in Krebs solutions whereas acetylcholine evoked contractions were still not reduced. These results suggested that the bathing solution and probably therefore the degree of ionisation of prostaglandin synthetase inhibitors were important in determining their potency. In the longitudinal muscle strip in which the Auerbachs plexus is exposed, prostaglandin synthetase inhibitors were 40-80 times more potent in inhibiting nicotine evoked and transmural stimulation evoked contractions than they were in the whole ileum preparation. This result suggested that diffusion was an important factor in determining the potency of prostaglandin synthetase inhibitors in thick tissue. Whenever the prostaglandin synthetase inhibitors reduced responses to nicotine or transmural stimulation, these responses were readily restored by the addition of 0.1 - 2.5 ngml⁻¹ PGE₂ but not PGF₂ Comparative studies with post junctional muacarinic receptor antagonists and ganglion blocking drugs showed that the site of action of prostaglandin synthetase inhibitors was not likely to be either the post junctional membrane or the ganglion. In the whole ileum preparation, the prostaglandin synthetase inhibitors reduced nicotine induced contractions more than those induced by transmural -timulation. Much higher concentrations were required to inhibit transmurally stimulated contractions. This suggests that the prostaglandin synthetase inhibitors were not acting by interfering with nerve impulse conduction. Indomethacin, sodium meclofenamate and ketoprofen (1 ugml⁻¹) reduced both basal and transmural stimulation induced release of acetylcholine from the longitudinal muscle strip at different frequencies of stimulation. The inhibitory action of prostaglandin synthetase inhibitors on acetylcholine output was reversed by PGE₂ (2.5 ngml⁻¹) but not PGG₂. It is proposed that prostaglandin synthetase inhibitors reduce the response to indirect stimuli by reducing acetylcholine output. The inhibition of acetylcholine release by prostaglandin synthetase inhibitors and its reversal by PGE₂ can be interpreted as a pharmacological interaction between the two agents; or it can be interpreted to mean that a prostaglandin plays a facilitatory role in acetylcholine release mechanism.