EM574, an erythromycin derivative, is a potent motilin receptor agonist in human gastric antrum

Erythromycin and its derivatives are known to induce phase III-like contractions, which are similar to those induced by motilin, in the human gastrointestinal tract during the interdigestive state, but few detailed in vitro studies have been reported. We evaluated EM574, an erythromycin derivative, as a motilin receptor agonist in the human gastric antrum in vitro, using contraction studies of muscle strips and isolated myocytes, receptor binding assay and tissue section autoradiography. EM574 stimulated contractions of muscle strips in a concentration-dependent manner (10(-7)-10(-5) M), and this contractile effect was unaffected by pretreatment with atropine or tetrodotoxin. Isolated myocytes contracted in response to EM574 with a peak shortening at 10(-7) M, which was comparable to the response to motilin. EM574 displaced specifically 125I-motilin bound to smooth muscle homogenates with a Kd value of 7.8 x 10(-9) M, compared with 4.5 x 10(-9) M for motilin. Film autoradiograms showed that 125I-motilin-binding sites were localized in the muscle layers, and that the labeling disappeared in the presence of a 1000 times molar concentration of EM574. We conclude that EM574 directly stimulates smooth muscle cell contraction by acting on motilin receptors in the human gastric antrum in vitro.