Effects of the benzodiazepine receptor agonist midazolam and antagonist flumazenil on 5-hydroxytryptamine release from guinea-pig intestine in vitro. Indirect support for a "natural" benzodiazepine-like substance in the intestine.
Isolated segments of the guinea-pig small intestine and the guinea-pig stomach were vascularly perfused and the release of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid into the portal venous effluent determined by high pressure liquid chromatography with electrochemical detection. Test substances were applied intraarterially. The benzodiazepine receptor agonist, midazolam, concentration-dependently increased (by 58%, at 1 nmol/l) and decreased (by 32%, at 100 nmol/l) the release of 5-HT from small intestine preparations. Both effects were blocked by the benzodiazepine receptor antagonist flumazenil (10 nmol/l) The stimulatory effect of midazolam was also abolished in the presence of tetrodotoxin (1 mumol/l) or scopolamine (100 nmol/l). In the absence of tetrodotoxin, flumazenil (10 nmol/l) alone decreased the release of 5-HT from the small intestine by 41%, but it increased the release of 5-HT by 50% in the presence of tetrodotoxin. Both effects of flumazenil were abolished in the presence of bicuculline (50 mumol/l). In the absence of tetrodotoxin, flumazenil (10 nmol/l) decreased also the release of 5-HT and its metabolite from the perfused stomach by about 40%, whereas midazolam (1 nmol/l) caused an increase by about 60%. In conclusion, benzodiazepine receptors modulate the previously described intrinsic GABAergic regulation of 5-HT release from enterochromaffin cells in the guinea-pig intestine. It is suggested that an endogenous benzodiazepine-like substance of non-neuronal origin is present in the small intestine and stomach of the guinea-pig.
Department of Pharmacology, University of Mainz, Federal Republic of Germany.
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Racké
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Schwörer
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Kilbinger
D000818:Animals; D002838:Chromaffin System / Q000166:cytology / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004563:Electrochemistry; D005260:Female; D005442:Flumazenil / Q000494:pharmacology*; D005753:Gastric Mucosa / Q000378:metabolism; D006168:Guinea Pigs; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008874:Midazolam / Q000494:pharmacology*; D010477:Perfusion; D011963:Receptors, GABA-A / Q000187:drug effects*; D012701:Serotonin / Q000378:metabolism*; D013270:Stomach / Q000187:drug effects; D013779:Tetrodotoxin / Q000494:pharmacology
D011963:Receptors, GABA-A; D012701:Serotonin; D005442:Flumazenil; D013779:Tetrodotoxin; D006897:Hydroxyindoleacetic Acid; D008874:Midazolam