AN ACTION OF ERYTHROMYCIN IN THE INTESTINE THAT IS NOT MEDIATED VIA MOTILIN RECEPTORS

1. Erythromycin lactobionate caused a concentration‐ dependent inhibition of nerve‐mediated contractions of the longitudinal muscle of the guinea‐pig ileum, with a threshold for effect of 10–30 μmol/L. The non‐antibiotic derivative of erythromycin ABT‐229 had a similar effect, but was approximately 10‐fold less potent. At a greater concentration (1 mmol/L), erythromycin also depressed the direct contractile effect of 10 μmol/L carbachol on the muscle.2. Human/porcine motilin (up to 100 μmol/L) did not reduce the nerve‐mediated contractions, although it did contract the muscle (threshold 30 μmol/L). Antagonists of motilin receptors (phe3leu13motilin, up to 1 μmol/L, and GM‐109, up to 3 μmol/L) did not reduce responses to erythromycin.3. Erythromycin contracted the longitudinal muscle of the rabbit duodenum, with a threshold concentration of 0.1 μmol/L and ABT‐229 contracted this tissue at a threshold concentration of 0.01 μmol/L. Effects of both agonists were antagonized by the motilin receptor antagonists phe3leu13motilin (0.3 μmol/L) and GM‐109 (1 μmol/L).4. It is concluded that the site(s) at which erythromycin acts in the guinea‐pig ileum is not a motilin receptor and that ABT‐229 is selective for the motilin receptor in comparison with non‐motilin erythromycin sites and is unlikely to act at the latter site in therapeutic doses.