Nicotinic and muscarinic modulation of 5-hydroxytryptamine (5-HT) release from porcine and canine small intestine.
Strips of porcine and canine small intestine were incubated in vitro and the release of 5-hydroxytryptamine (5-HT) was determined by HPLC with electrochemical detection. The spontaneous outflow of 5-HT from the porcine and canine small intestine largely reflects calcium-dependent 5-HT secretion from enterochromaffin cells which are under a spontaneous neuronal, excitatory input as indicated by the inhibitory effect (30-40%) of tetrodotoxin. In both species, nicotine enhanced the release of 5-HT in a concentration-dependent manner by a maximum of about 50% at 100 microM. This effect was blocked by the nicotine receptor antagonist hexamethonium, but not by the subtype-selective nicotine receptor antagonist alpha-bungarotoxin. The effect of nicotine was rapidly desensitized. The presence of tetrodotoxin abolished the effect of nicotine on 5-HT release in canine tissue but not in porcine tissue. The presence of the muscarine receptor antagonist scopolamine prevented the effect of nicotine on 5-HT release from canine tissue, but significantly enhanced 5-HT release from porcine tissue. The muscarine receptor agonist oxotremorine inhibited 5-HT release from porcine tissue, but increased 5-HT release from canine tissue. However, in the presence of tetrodotoxin, oxotremorine enhanced 5-HT release in tissue from both species. In conclusion, activation of nicotine receptors induce the release of 5-HT from porcine and canine small intestine. In the dog, the effect of nicotine is mediated via the release of acetylcholine which then stimulates 5-HT release via muscarine receptors on the enterochromaffin cells. In the pig, the stimulatory effect of nicotine appears to be located directly on the enterochromaffin cells. In addition, activation of neuronal muscarine receptors in the porcine small intestine induced the release of a previously unidentified neurotransmitter which inhibited 5-HT release. Nicotine, via cholinergic interneurons, also appears to induce the release of this inhibitory neurotransmitter which opposes the direct stimulatory action of nicotine on 5-HT release.
Racké
K
K
Pharmakologisches Institut, Johannes Gutenberg-Universität Mainz.
Schwörer
H
H
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D002038:Bungarotoxins / Q000494:pharmacology; D002118:Calcium / Q000502:physiology; D004246:Dimethylphenylpiperazinium Iodide / Q000494:pharmacology; D004285:Dogs; D004759:Enterochromaffin Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D018738:Hexamethonium; D006584:Hexamethonium Compounds / Q000494:pharmacology; D006897:Hydroxyindoleacetic Acid / Q000032:analysis; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009538:Nicotine / Q000494:pharmacology; D010095:Oxotremorine / Q000494:pharmacology; D010276:Parasympatholytics / Q000494:pharmacology*; D010277:Parasympathomimetics / Q000494:pharmacology*; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology*; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000502:physiology*; D012601:Scopolamine / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism*; D013552:Swine; D013779:Tetrodotoxin / Q000494:pharmacology
D002038:Bungarotoxins; D006584:Hexamethonium Compounds; D010276:Parasympatholytics; D010277:Parasympathomimetics; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D012701:Serotonin; D018738:Hexamethonium; D013779:Tetrodotoxin; D006897:Hydroxyindoleacetic Acid; D004246:Dimethylphenylpiperazinium Iodide; D010095:Oxotremorine; D009538:Nicotine; D012601:Scopolamine; D000109:Acetylcholine; D002118:Calcium