Effects of EM574 and cisapride on gastric contractile and emptying activity in normal and drug-induced gastroparesis in dogs.
EM574, an erythromycin derivative and potent motilin receptor agonist, is now undergoing clinical trials as a gastroprokinetic drug. The aim of this study was to compare the effect of EM574 with that of cisapride on gastric motility and emptying in normal and gastroparesis dogs. Six dogs were each implanted with two duodenal cannulas for infusion of phenolsulfonphthalein into the proximal duodenum and for aspiration of luminal samples from the distal duodenum. Both solid and liquid gastric emptying were determined by a novel freeze-drying method developed in our laboratory. A freeze-dried standard meal (100 g, 400 kcal) was given with 100 ml normal saline containing 15 g of polyethylene glycol as a liquid marker. Gastric muscle contractility was measured by means of a force transducer implanted on the gastric antrum. EM574 (3-30 microgram/kg) and cisapride (0.3-3.0 mg/kg) were administered intraduodenally at the start of feeding. Clonidine (3-30 microgram/kg) was injected subcutaneously 15 min before feeding to induce gastroparesis. EM574 and cisapride both enhanced gastric muscle contractility in a dose-dependent manner. EM574 (30 microgram/kg and 10 microgram/kg) significantly accelerated gastric emptying of solids and liquids, respectively. Cisapride (1 mg/kg) significantly accelerated solid gastric emptying, but 3.0 mg/kg significantly delayed liquid gastric emptying. Clonidine (10 and 30 microgram/kg) significantly delayed solid and liquid gastric emptying and reduced gastric muscle contractility. EM574, at a dose of 30 microgram/kg, completely restored solid and liquid gastric emptying and muscle contractility to the normal range in dogs with clonidine-induced gastroparesis. Cisapride (1 mg/kg) restored liquid gastric emptying in dogs with gastroparesis to the normal range and partially restored solid emptying. EM574 accelerated gastric muscle contractility and emptying of solids and liquids in normal dogs. The stimulating activity of EM574 on gastric muscle contractility and emptying was comparable to that of cisapride, but EM574 was as effective as cisapride in normalizing gastric muscle contractility and emptying in dogs with clonidine-induced gastroparesis.
Tanaka
T
T
Gastrointestinal Research Laboratory, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan.
Mizumoto
A
A
Mochiki
E
E
Suzuki
H
H
Itoh
Z
Z
Omura
S
S
D000818:Animals; D020117:Cisapride / Q000494:pharmacology*; D003000:Clonidine / Q000494:pharmacology; D004285:Dogs; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D005746:Gastric Emptying / Q000187:drug effects*; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D018589:Gastroparesis / Q000139:chemically induced / Q000503:physiopathology*; D009119:Muscle Contraction / Q000187:drug effects; D019518:Postprandial Period; D013270:Stomach / Q000187:drug effects / Q000502:physiology
D005765:Gastrointestinal Agents; C090116:Idremcinal; D004917:Erythromycin; D003000:Clonidine; D020117:Cisapride