H. Kilbinger et al., BENZIMIDAZOLONES AND RENZAPRIDE FACILITATE ACETYLCHOLINE-RELEASE FROMGUINEA-PIG MYENTERIC PLEXUS VIA 5-HT4 RECEPTORS, Naunyn-Schmiedeberg's archives of pharmacology, 351(3), 1995, pp. 229-236
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 ele
ctrically evoked outflow of tritium were studied in guineapig longitud
inal muscle myenteric plexus preparations preincubated with [H-3]choli
ne. Muscle contractions were recorded simultaneously. BIMU 8 caused a
calcium dependent and tetrodotoxin sensitive increase in basal [H-3]ou
tflow 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 t
ropisetron (each 1 mu mol/l) competitively antagonized the various fac
ilitatory effects of BIMU 8 with pA(2) values of 7.0-7.2 (DAU 6285) an
d 7.0-7.3 (tropisetron). The phosphodiesterase inhibitors IBMX and rol
ipram did not increase the effects of BIMU 8. BIMU 1 and renzapride al
so concentration-dependently increased basal release of acetylcholine,
and release and contractions caused by submaximal stimulation. The ef
fects 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 acetyl
choline and contractions elicited by submaximal stimulation were stron
gly inhibited by (+)-tubocurarine which indicates that nicotinic gangl
ionic transmission is involved in this kind of release. The results su
ggest 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 invol
ved in the 5-HT4 receptor mediated facilitation of acetylcholine relea
se.