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Br J Pharmacol. 2004 Feb;141(4):600-9. Epub 2004 Jan 26.

E-ring 8-isoprostanes inhibit ACh release from parasympathetic nerves innervating guinea-pig trachea through agonism of prostanoid receptors of the EP3-subtype.

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  • 1Respiratory Pharmacology Group, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, Guy Scadding Building, Dovehouse Street, London SW3 6LY.


1. In the present study, we examined the effect of E-ring 8-isoprostanes on cholinergic neurotransmission in guinea-pig trachea and identified the receptor(s) involved. As isoprostanes are isomeric with prostaglandins, PGE(2) and sulprostone (a selective EP(3)-receptor agonist) were examined in parallel. 2. 8-Iso-PGE(1), 8-iso-PGE(2) (0.1 nm-1 microM), sulprostone (1 nm-1 microM) and PGE(2) (1 microM) suppressed EFS-evoked [(3)H]ACh release from guinea-pig trachea in a concentration-dependent manner, producing 39.5, 53.9, 61.2 and 59.9% inhibition, respectively, at 1 microM. It should be noted that an established maximum effective concentration was not determined. 3. Neither SQ 29,548 (1 microm; a TP-receptor antagonist) nor AH 6809 (10 microM; an EP(1)-/EP(2)-/DP-receptor antagonist) reversed the inhibitory effect of these compounds. 4. L-798,106, a novel and highly selective EP(3)-receptor antagonist, produced a parallel shift to the right of the concentration-response curves that described the inhibitory action of sulprostone on EFS-evoked contractile responses in guinea-pig vas deferens (an established EP(3)-receptor-expressing tissue), from which a mean pA(2) of 7.48 was derived. On guinea-pig trachea, L-798,106 also antagonised sulprostone-induced inhibition of EFS-induced twitch responses, with similar potency (mean pA(2)=7.82). 5. The inhibitory effects of 8-iso-PGE(1), 8-iso-PGE(2), sulprostone and PGE(2) on EFS-induced [(3)H]ACh release was blocked by L-798,106 at a concentration (10 microM) that binds only weakly to human recombinant EP(1)-, EP(2)- and EP(4)-receptor subtypes expressed in HEK 293 cells. 6. These data suggest that E-ring 8-isoprostanes, PGE(2) and sulprostone inhibit EFS-evoked [(3)H]ACh release from cholinergic nerves innervating guinea-pig trachea, by interacting with prejunctional prostanoid receptors of the EP(3)-subtype.

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