Effects of 5-HT4 receptor stimulation on basal and electrically evoked release of acetylcholine from guinea-pig myenteric plexus.
The effects of 5-methoxytryptamine and 5-hydroxytryptamine (5-HT) on both basal and electrically evoked outflow of tritium were studied in guinea-pig myenteric plexus preparations preincubated with [3H]-choline. Basal outflow. 5-Methoxytryptamine caused a transient and calcium-dependent increase in basal outflow of [3H]acetylcholine that was abolished by tetrodotoxin. Ondansetron (1 mumol/l) did not affect the stimulatory response of 5-methoxytryptamine but ICS 205-930 (1 and 3 mumol/l) produced parallel rightward displacements of the concentration-response curve to 5-methoxytryptamine. The pKB value for ICS 205-930 was 6.6 suggesting an involvement of 5-HT4 receptors. 5-HT caused an increase in basal outflow of [3H]acetylcholine and a biphasic concentration-response curve was obtained. The maximal response of the first phase to 5-HT (release of 0.98% of tissue tritium) and the maximal response to 5-methoxytryptamine (0.94% of tissue tritium) were similar but 5-methoxytryptamine (-log EC50: 6.9) was less potent than 5-HT (-log EC50 of the high affinity component: 7.9). ICS 205-930 (0.01-1.0 mumol/l) acted as a competitive antagonist against the low affinity component of the 5-HT concentration-response curve with a pA2 value of 8.0. It is concluded that stimulation of both 5-HT4 receptors (by 5-methoxytryptamine and submicromolar concentrations of 5-HT) and 5-HT3 receptors (by micromolar concentrations of 5-HT) causes a release of acetylcholine which in turn leads to smooth muscle contraction. Electrically evoked outflow. This outflow of [3H]-acetylcholine was concentration-dependently inhibited by both 5-methoxytryptamine and 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)
Kilbinger
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H
Pharmakologisches Institut, Universität Mainz, Federal Republic of Germany.
Wolf
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D
D008735:5-Methoxytryptamine / Q000494:pharmacology; D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D002794:Choline / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004558:Electric Stimulation; D005260:Female; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000294:innervation; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000294:innervation; D009197:Myenteric Plexus / Q000378:metabolism* / Q000648:ultrastructure; D009469:Neuromuscular Junction / Q000187:drug effects / Q000502:physiology; D011985:Receptors, Serotonin / Q000145:classification / Q000187:drug effects / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology; D013268:Stimulation, Chemical; D014316:Tritium
D002800:Cholinesterase Inhibitors; D011985:Receptors, Serotonin; D014316:Tritium; D012701:Serotonin; D008735:5-Methoxytryptamine; D002794:Choline; D000109:Acetylcholine