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

Abstract

1. 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.

2. 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, PGF_2α 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.

3. 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 PGF_2α.

4. 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.

5. 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.

6. 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.

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