AS-4370, a new gastrokinetic agent, enhances upper gastrointestinal motor activity in conscious dogs.
The effects of AS-4370 [4-amino-5-chloro-2-ethoxy-N-(4-(4-fluorobenzyl)-2 morpholinyl)methyl)benzamide citrate] on gastrointestinal (GI) motor activity were compared with those of cisapride and metoclopramide in conscious dogs with force transducers implanted chronically. In postprandial state, AS-4370 given 0.2 to 1 mg/kg i.v. or 1 mg/kg intraduodenally (i.d.) stimulated the antral and duodenal motor activity without affecting the colonic motor activity. Cisapride at 0.2 to 1 mg/kg i.v. or 1 mg/kg i.d. stimulated the motor activity in all sites of the GI tract from the stomach to the colon simultaneously. Metoclopramide, like AS-4370, stimulated the antral and duodenal motor activity, but its effect was less potent than that of AS-4370. AS-4370 did not stimulate the GI motor activity under treatment with atropine but stimulated it under vagotomy. Furthermore, AS-4370 did not potentiate the methacholine-induced antral contraction, whereas neostigmine at 10 micrograms/kg i.v. significantly enhanced it. AS-4370 at 1 mg/kg i.v. did not antagonize the inhibition of antral motor activity induced by i.v. infusion of dopamine (1 mg/kg/hr), whereas cisapride (0.5 mg/kg i.v.) and metoclopramide (1 mg/kg i.v.) antagonized it. In addition, the enhancement of GI motor activity induced by AS-4370 was not prevented by propranolol, prazosin, yohimbine, methysergide, ketanserin, ICS 205-930 or naloxone. 5- Hydroxytryptamine (5-HT) receptor desensitization induced by 5-HT (300 micrograms/kg/hr) in the antrum reduced the enhancement induced by AS-4370.(ABSTRACT TRUNCATED AT 250 WORDS)
Yoshida
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N
Department of Pharmacology, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
Ito
T
T
Karasawa
T
T
Itoh
Z
Z
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D020117:Cisapride; D004285:Dogs; D004386:Duodenum / Q000187:drug effects; D005260:Female; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D005769:Gastrointestinal Motility / Q000187:drug effects*; D007583:Jejunum / Q000187:drug effects; D008297:Male; D008787:Metoclopramide / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D011706:Pyloric Antrum / Q000187:drug effects* / Q000502:physiology; D012702:Serotonin Antagonists / Q000494:pharmacology
D001549:Benzamides; D005765:Gastrointestinal Agents; D009025:Morpholines; D010880:Piperidines; D012702:Serotonin Antagonists; C062720:mosapride; D008787:Metoclopramide; D020117:Cisapride