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- Title
E-Ring 8-isoprostanes inhibit ACh release from parasympathetic nerves innervating guinea-pig trachea through agonism of prostanoid receptors of the EP<sub>3</sub>-subtype.
- Authors
Clarke, Deborah L.; Giembycz, Mark A.; Patel, Hema J.; Belvisi, Maria G.
- Abstract
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, PGE2 and sulprostone (a selective EP3-receptor agonist) were examined in parallel. 2: 8-Iso-PGE1, 8-iso-PGE2 (0.1?nM-1?µM), sulprostone (1?nM-1?µM) and PGE2 (1?µM) suppressed EFS-evoked [3H]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?µM. It should be noted that an established maximum effective concentration was not determined. 3: Neither SQ 29,548 (1?µM; a TP-receptor antagonist) nor AH 6809 (10?µM; an EP1-/EP2-/DP-receptor antagonist) reversed the inhibitory effect of these compounds. 4: L-798,106, a novel and highly selective EP3-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 EP3-receptor-expressing tissue), from which a mean pA2 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 pA2=7.82). 5: The inhibitory effects of 8-iso-PGE1, 8-iso-PGE2, sulprostone and PGE2 on EFS-induced [3H]ACh release was blocked by L-798,106 at a concentration (10?µM) that binds only weakly to human recombinant EP1-, EP2- and EP4-receptor subtypes expressed in HEK 293 cells. 6: These data suggest that E-ring 8-isoprostanes, PGE2 and sulprostone inhibit EFS-evoked [3H]ACh release from cholinergic nerves innervating guinea-pig trachea, by interacting with prejunctional prostanoid receptors of the EP3-subtype.British Journal of Pharmacology (2004) 141, 600-609. doi:10.1038/sj.bjp.0705648
- Publication
British Journal of Pharmacology, 2004, Vol 141, Issue 4, p600
- ISSN
0007-1188
- Publication type
Academic Journal
- DOI
10.1038/sj.bjp.0705648