Presynaptic modulation of cholinergic neurotransmission in the human proximal stomach

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Abstract
This study investigates whether the cholinergic neurones, innervating the human proximal stomach, can be modulated by nitric oxide (NO) or vasoactive intestinal polypeptide (VIP), orviapresynaptic muscarinic, α2‐ or 5‐hydroxytryptamine4(5‐HT4‐) receptors. Circular muscle strips, without mucosa, were incubated with [3H]‐choline to incorporate [3H]‐acetylcholine into the cholinergic transmitter stores. The basal and electrically‐induced release of tritium and [3H]‐acetylcholine were analysed in a medium containing guanethidine (4×10−6 M), hemicholinium‐3 (10−5 M), physostigmine (10−5 M) and atropine (10−6 M). Tissues were stimulated twice for 2 min (S1and S2: 40 V, 1 ms, 4 Hz) and drugs were added before S2. The NO synthase inhibitorL‐NG‐nitroarginine methyl ester (3×10−4 M) and the NO donor sodium nitroprusside (10−5 M), as well as VIP (10−7 M) did not influence the basal release nor the electrically‐evoked release. The α2‐adrenoceptor agonist UK‐14,304 (10−5 M) significantly inhibited the electrically‐evoked release of [3H]‐acetylcholine, and this was prevented by the α2‐adrenoceptor antagonist rauwolscine (2×10−6 M). The 5‐HT4‐receptor agonist prucalopride (3×10−7 M) significantly enhanced the electrically‐evoked release of [3H]‐acetylcholine, and the 5‐HT4‐receptor antagonist SB204070 (10−9 M) prevented this. When atropine (10−6 M) was omitted from the medium and added before the second stimulation, it significantly increased the release of [3H]‐acetylcholine. These results suggest that the release of acetylcholine from the cholinergic neurones, innervating the circular muscle in the human proximal stomach, can be inhibitedviapresynaptic muscarinic auto‐receptors and α2‐adrenoceptors, and stimulatedviapresynaptic 5‐HT4‐receptors. No evidence for modulation by NO or VIP was obtained. British Journal of Pharmacology(2002)135, 135–142; doi:10.1038/sj.bjp.0704471

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