Prostaglandin E 2 suppression of acetylcholine release from parasympathetic nerves innervating guinea‐pig trachea by interacting with prostanoid receptors of the EP 3 ‐subtype

1 We have demonstrated recently that exogenous prostaglandin E 2 (PGE 2 ) 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 PGE 2 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 [ 3 H]‐ACh release. 2 In epithelium‐denuded tracheal strips pretreated with indomethacin (10 μ M ), PGE 2 (0.1 n M –1 μ M ) inhibited EFS‐evoked [ 3 H]‐ACh release in a concentration‐dependent manner with an EC 50 and maximal effect of 7.62 n M and 74% inhibition, respectively. Cicaprost, an IP‐receptor agonist, PGF 2α and the stable thromboxane mimetic, U46619 (each at 1 μ M ), also inhibited [ 3 H]‐ACh release by 48%, 41% and 35%, respectively. PGD 2 (1 μ M ) had no significant effect on [ 3 H]‐ACh release. 3 The selective TP‐receptor antagonist, ICI 192,605 (0.1 μ M ), completely reversed the inhibition of cholinergic neurotransmission induced by U‐46619, but had no significant effect on similar responses effected by PGE 2 and PGF 2α . 4 A number of EP‐receptor agonists mimicked the ability of PGE 2 to inhibit [ 3 H]‐ACh release with a rank order of potency: GR63799X (EP 3 ‐selective)>PGE 2 >M&B 28,767 (EP 3 selective)>17‐phenyl‐ω‐trinor PGE 2 (EP 1 ‐selective). The EP 2 ‐selective agonist, AH 13205 (1 μ M ), did not affect EFS‐induced [ 3 H]‐ACh release. 5 AH6809 (10 μ M ), at a concentration 10 to 100 times greater than its pA 2 at DP‐, EP 1 ‐ and EP 2 ‐receptors, failed to reverse the inhibitory effect of PGE 2 or 17‐phenyl‐ω‐trinor PGE 2 on [ 3 H]‐ACh release. 6 These results suggest that PGE 2 inhibits [ 3 H]‐ACh release from parasympathetic nerves supplying guinea‐pig trachea via an interaction with prejunctional prostanoid receptors of the EP 3 ‐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 [ 3 H]‐ACh release when compared to receptors of the EP 3 ‐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