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 guinea-pig longitudinal muscle myenteric plexus preparations preincubated with [3H]choline. Muscle contractions were recorded simultaneously. BIMU 8 caused a calcium dependent and tetrodotoxin sensitive increase in basal [3H]outflow that was assumed to represent release of [3H]acetylcholine. In addition, BIMU 8 enhanced the release of [3H]acetylcholine and twitch contractions evoked by submaximal electrical stimulation. Ondansetron (1 mumol/l) did not change the effects of BIMU 8, but DAU 6285 and tropisetron (each 1 mumol/l) competitively antagonized the various facilitatory effects of BIMU 8 with pA2 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 mumol/l tropisetron (pA2 6.6-7.1). The EC50 values for the increase in the evoked [3H]acetylcholine release and contractions were closely similar. 5-Hydroxyindalpine did not change basal release and slightly inhibited the evoked release of [3H]acetylcholine. Release of acetylcholine and contractions elicited by submaximal stimulation were strongly inhibited by (+)-tubocurarine which indicates that nicotine 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Kilbinger
H
H
Department of Pharmacology, University of Mainz, Germany.
Gebauer
A
A
Haas
J
J
Ladinsky
H
H
Rizzi
C A
CA
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002794:Choline / Q000378:metabolism; D004558:Electric Stimulation; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009197:Myenteric Plexus / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D001549:Benzamides; D001562:Benzimidazoles; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D010726:Phosphodiesterase Inhibitors; D010880:Piperidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C070187:(endo-N-8-methyl-8-azabicyclo(3.2.1)oct-3-yl)-2,3-dihydro-3-ethyl-2-oxo-1H-benzimidazol-1-carboxamide; C070189:(endo-N-8-methyl-8-azabicyclo-(3.2.1)oct-3-yl)-2,3-dihydro-3-isopropyl-2-oxo-1H-benzimidazol-1-carboxamide; C059798:5-hydroxyindalpine; C053006:renzapride; D002794:Choline; D000109:Acetylcholine