Prostanoid receptors of the EP3 subtype mediate inhibition of evoked [3H]acetylcholine release from isolated human bronchi

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Abstract
The release of neuronal [3H]acetylcholine (ACh) from isolated human bronchi after labelling with [3H]choline was measured to investigate the effects of prostanoids. A first period of electrical field stimulation (S1) caused a [3H]ACh release of 320±70 and 200±40 Becquerel (Bq) g−1 in epithelium‐denuded and epithelium‐containing bronchi respectively (P>0.05). Subsequent periods of electrical stimulation (Sn, n=2, 3, and 4) released less [3H]ACh, i.e. decreasing Sn/S1 values were obtained (0.76±0.09, 0.68±0.07 and 0.40±0.04, respectively). Cumulative concentrations (1–1000 nM) of EP‐receptor agonists like prostaglandin E2, nocloprost, and sulprostone (EP1 and EP3 selective) inhibited evoked [3H]ACh release in a concentration dependent manner with IC50 values between 4–14 nM and maximal inhibition of about 70%. The inhibition of evoked [3H]ACh release by prostaglandin E2, nocloprost and sulprostone was not affected by the DP‐, EP1‐ and EP2‐receptor antagonist AH6809 at a concentration of 3 μM, i.e. a 3–30 times greater concentration than its affinity (pA2 values) at the respective receptors. Circaprost (IP‐receptor agonist; 1–100 nM), iloprost (IP‐ and EP1‐receptor agonist; 10‐1000 nM) and U‐46619 (TP‐receptor agonist; 100–1000 nM) did not significantly affect [3H]ACh release. Blockade of cyclooxygenase by 3 μM indomethacin did not significantly modulate evoked [3H]ACh release in epithelium‐containing and epithelium‐denuded bronchi. Likewise, the combined cyclo‐ and lipoxygenase inhibitor BW‐755C (20 μM) did not affect evoked [3H]ACh release. In conclusion, applied prostanoids appear to inhibit [3H]ACh release in epithelium‐denuded human bronchi under the present in vitro conditions, most likely via prejunctional prostanoid receptors of the EP3 subtype. British Journal of Pharmacology (1998) 125, 271–276; doi:10.1038/sj.bjp.0702057