BENZIMIDAZOLONES AND RENZAPRIDE FACILITATE ACETYLCHOLINE-RELEASE FROM GUINEA-PIG MYENTERIC PLEXUS VIA 5-HT4 RECEPTORS

The effects of the 5-HT4 receptor agonists BIMU 8, BIMU 1, renzapride and of the 5-HT1p receptor agonist 5-hydroxyindalpine on basal and electrically evoked outflow of tritium were studied in guineapig longitudinal muscle myenteric plexus preparations preincubated with [H-3]choline. Muscle contractions were recorded simultaneously. BIMU 8 caused a calcium dependent and tetrodotoxin sensitive increase in basal [H-3]outflow that was assumed to represent release of [H-3]acetylcholine. In addition, BIMU 8 enhanced the release of [H-3]acetylcholine and twitch contractions evoked by submaximal electrical stimulation. Ondansetron (1 mu mol/l) did not change the effects of BIMU 8, but DAU 6285 and tropisetron (each 1 mu mol/l) competitively antagonized the various facilitatory effects of BIMU 8 with pA(2) values of 7.0-7.2 (DAU 6285) and 7.0-7.3 (tropisetron). The phosphodiesterase inhibitors IBMX and rolipram did not increase the effects of BIMU 8. BIMU 1 and renzapride also concentration-dependently increased basal release of acetylcholine, and release and contractions caused by submaximal stimulation. The effects of BIMU 1 and renzapride were competitively antagonized by 1 mu mol/l tropisetron (pA(2) 6.6-7.1). The EC(50) values for the increase in the evoked [H-3]acetylcholine release and contractions were closely similar. 5-Hydroxyindalpine did not change basal release and slightly inhibited the evoked release of [H-3]acetylcholine. Release of acetylcholine and contractions elicited by submaximal stimulation were strongly inhibited by (+)-tubocurarine which indicates that nicotinic ganglionic transmission is involved in this kind of release. The results suggest that BIMU 8, BIMU 1 and renzapride stimulate 5-HT4 receptors at cholinergic interneurones and thereby facilitate nicotinic ganglionic transmission in the myenteric plexus. Cyclic AMP is probably not involved in the 5-HT4 receptor mediated facilitation of acetylcholine release.