T1359 Prostaglandin EP 3 Receptor-Mediated Disruption of Gastric Slow Wave Rhythm and Coupling Measured By Multichannel Mucosal Mapping in An In Vivo Canine Model

Abstract

Background: Prostaglandin synthesis inhibitors (e.g. indomethacin) prevent gastric slow wave dysrhythmias in humanmodels, showing endogenous prostaglandins disrupt slowwave cycling. In isolated tissues, prostaglandin EP3 agonists elicit slow wave rhythm disturbances. Prostaglandin infusion evokes dysrhythmias in an In Vivo canine model, but roles of different EP receptors are unexplored. Regional differences in actions of EP agonists on In Vivo slow waves are unknown. Aims: (i) To compare dose-dependent effects of intravenous prostaglandin E2 (PGE2), butaprost (EP2 agonist), and sulprostone (EP3 agonist) on slow wave rhythm and coupling In Vivo and (ii) to contrast regional responses of the corpus to the antrum. Methods: 6 female dogs (18-25 kg) underwent slow wave mapping on separate days under 3 conditions (PGE2, butaprost, and sulprostone). After overnight fasting, endoscopy was performed with midazolam and ketamine and a catheter with 3 bipolar electrodes was affixed to the mucosa using endoclips 2, 7 and 17 cm from the pylorus. Multichannel recordings were obtained x 30 min under control conditions, and with low, medium, and high dose infusions of the test agents. Slow wave parameters at each recording site were % time in normal frequency (3.7-6.3 cycles per min[cpm]), bradygastria ( 6.3 cpm). Corpus-antrum coupling was calculated by commercial software (AcqKnowledge). Results: In control recordings, % time in normal rhythm was 61±7% proximally, 58±10% in the middle lead, and 84±3% distally. Corpus-antrum coupling was 78±4%. Low-dose PGE2 (35 μg/kg/h) reduced time in normal rhythm to 64±14% (P=0.05) and increased time in bradygastria from 9±2 to 22±6% (P=0.02) distally but did not induce tachygastria and had no effect on normal rhythm (61±4%) proximally. Coupling decreased to 69±5% with PGE2 (P=0.01). Higher PGE2 doses did not have additional effect. Mediumdose sulprostone (0.15 μg/kg/min) reduced normal rhythm to 60±7% (P=0.01) and increased bradygastria to 18±2% (P=0.01) distally but did not alter proximal normal rhythm (70.3+11.4%). High dose sulprostone (0.5 μg/kg/min) decreased coupling to 72±7% (P= 0.02). High-dose butaprost (0.5 μg/kg/min) did not affect distal (71±14%) or proximal (60±13%) normal rhythm or coupling (77±15%). Conclusions: Prostaglandin E2 promotes loss of normal slow wave rhythm in an In Vivo canine model with induction of bradygastria and uncoupling that are restricted to the antrum. These effects are mimicked by the EP3 agonist sulprostone but not the EP2 agonist butaprost. Thus as in excised tissues, prominent slow wave disruption is observed with EP3 receptor agonism in whole animals.