The gastroprokinetic effects of de(N-methyl)-N-isopropyl-8, 9-anhydroerythromycin A 6,9-hemiacetal (
EM574), a non-
peptide motilin receptor agonist, were investigated in conscious dogs in a normal state and with experimentally-induced
gastroparesis. Gastric emptying of semi-solid meals was assessed indirectly from
acetaminophen absorption with simultaneous recording of gastric
antral motility. In the normal state, post-prandial intraduodenal administration of
EM574 (0.03 mg/kg) [corrected] stimulated
antral motility and significantly enhanced gastric emptying as potently as did intravenous porcine
motilin (0.003 mg/kg/h). Intraduodenal
cisapride at 1 mg/kg denal
cisapride at 1 mg/kg elicited
antral contractions and tended to accelerate gastric emptying but at 3 mg/kg, gastric emptying was not enhanced despite a further increase in the motor index. In dogs with
gastroparesis induced by intraduodenal
oleic acid or intravenous
dopamine,
EM574 (0.03 mg/kg) increased
antral motility and reversed the delayed gastric emptying completely.
Cisapride (1 mg/kg) partially ameliorated the impaired emptying under these conditions. In atropinized dogs, no acceleration of gastric emptying by
EM574 was observed. These results indicate that
EM574 potently accelerates gastric emptying of caloric meals in dogs in a normal state and with experimentally-induced
gastroparesis, and also suggest that the effect is mediated through stimulation of a
cholinergic neural pathway.