Down-regulation of motilin receptors on rabbit colon myocytes by chronic oral erythromycin.

Acutely, erythromycin stimulates colonic smooth muscle contraction via action on motilin receptors, but the effects of chronic erythromycin exposure are unknown. Thus contraction and motilin binding studies were performed on rabbit colonic smooth muscle after 2 weeks of oral erythromycin ethyl succinate (25 mg/kg, twice a day). Isolated colon myocytes from untreated rabbits contracted to erythromycin with an EC50 of 30 +/- 17 pM and peak shortening of 24.1 +/- 0.8% at 10 nM. Motilin evoked similar contractions with an EC50 of 63 +/- 13 pM and peak shortening of 26.8 +/- 0.9% at 10 nM. Myocytes from treated rabbits exhibited reduced contractile responses to erythromycin with an EC50 of 203 +/- 27 pM (P < .002) and decreased peak shortening to 20.1 +/- 2.9% at 100 nM (P < .05). Motilin responses were also blunted [EC50 of 326 +/- 16 pM, peak shortening of 16.2 +/- 1.2% at 1 microM (P < .002)]. [125I]motilin binding to untreated colon smooth muscle homogenates was saturable and specific with a Kd of 0.53 +/- 0.10 nM and a Bmax of 48 +/- 6 fmol/mg protein. Muscle from treated rabbits exhibited no change in motilin receptor affinity (Kd = 0.50 +/- 0.08 nM) but showed a 63% reduction in receptor density (Bmax = 18 +/- 4 fmol/mg protein; P < .03). In conclusion, chronic erythromycin administration results in decreased contractile potency and efficacy of motilin and erythromycin on colonic myocytes, associated with decreased motilin receptor density but no change in receptor affinity. Thus chronic erythromycin exposure leads to tolerance to its colonic smooth muscle motor effects via motilin receptor down-regulation.