Prostaglandin E2 suppression of acetylcholine release from parasympathetic nerves innervating guinea‐pig trachea by interacting with prostanoid receptors of the EP3‐subtype

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Abstract
We have demonstrated recently that exogenous prostaglandin E2 (PGE2) inhibits electrical field stimulation (EFS)‐induced acetylcholine (ACh) release from parasympathetic nerve terminals innervating guinea‐pig trachea. In the present study, we have attempted to characterize the pre‐junctional prostanoid receptor(s) responsible for the inhibitory action of PGE2 and to assess whether other prostanoids modulate, at a prejunctional level, cholinergic neurotransmission in guinea‐pig trachea. To this end, we have investigated the effect of a range of both natural and synthetic prostanoid agonists and antagonists on EFS‐evoked [3H]‐ACh release. In epithelium‐denuded tracheal strips pretreated with indomethacin (10 μM), PGE2 (0.1 nM–1 μM) inhibited EFS‐evoked [3H]‐ACh release in a concentration‐dependent manner with an EC50 and maximal effect of 7.62 nM and 74% inhibition, respectively. Cicaprost, an IP‐receptor agonist, PGF2α and the stable thromboxane mimetic, U46619 (each at 1 μM), also inhibited [3H]‐ACh release by 48%, 41% and 35%, respectively. PGD2 (1 μM) had no significant effect on [3H]‐ACh release. The selective TP‐receptor antagonist, ICI 192,605 (0.1 μM), completely reversed the inhibition of cholinergic neurotransmission induced by U‐46619, but had no significant effect on similar responses effected by PGE2 and PGF2α. A number of EP‐receptor agonists mimicked the ability of PGE2 to inhibit [3H]‐ACh release with a rank order of potency: GR63799X (EP3‐selective)>PGE2>M&B 28,767 (EP3 selective)>17‐phenyl‐ω‐trinor PGE2 (EP1‐selective). The EP2‐selective agonist, AH 13205 (1 μM), did not affect EFS‐induced [3H]‐ACh release. AH6809 (10 μM), at a concentration 10 to 100 times greater than its pA2 at DP‐, EP1‐ and EP2‐receptors, failed to reverse the inhibitory effect of PGE2 or 17‐phenyl‐ω‐trinor PGE2 on [3H]‐ACh release. These results suggest that PGE2 inhibits [3H]‐ACh release from parasympathetic nerves supplying guinea‐pig trachea via an interaction with prejunctional prostanoid receptors of the EP3‐receptor subtype. Evidence for inhibitory prejunctional TP‐ and, possibly, IP‐receptors was also obtained although these receptors may play only a minor role in suppressing [3H]‐ACh release when compared to receptors of the EP3‐subtype. However, the relative importance of the different receptors will depend not only on the sensitivity of guinea‐pig trachea to prostanoids but on the nature of the endogenous ligands released locally that have activity on parasympathetic nerves. British Journal of Pharmacology (1998) 123, 1246–1252; doi:10.1038/sj.bjp.0701720