Direct inhibitory effect of erythromycin on the gallbladder muscle

Erythromycin, a macrolide antibiotic, stimulates motor activity in various parts of the gastrointestinal tract in humans and animals. This effect of erythromycin resembles that of motilin, a gastrointestinal hormone, in evoking contractions similar to phase 3 activity of the migrating motor complex. Motilin induces contractions in the canine gallbladder but fails to evoke any response, either in vivo or in vitro, in the human gallbladder. Surprisingly, erythromycin stimulates human gallbladder emptying in healthy volunteers and in persons with diabetic autonomic neuropathy. In the present study we examined the effect of erythromycin on chemically and electrically evoked contractions of isolated gallbladders from guinea pigs and humans by use of isometric force measurements. Carbachol, a muscarinic cholinergic agonist, evoked gallbladder contractions that were diminished by erythromycin in a concentration-dependent manner: at 200 micromol/L the contractions were 86% +/- 20% of the control response, at 500 micromol/L they were 63% +/- 21% of control, and at 1000 micromol/L they were 41% +/- 20% of control (P <0.05, N = 10, mean +/- standard deviation). Electrically evoked gallbladder contractions were reduced to 68% +/- 18% of the control response with the addition of 500 micromol/L of erythromycin and to 56% +/- 19% of control after the addition of 1000 micromol/L (P <0.05, N = 8). Guinea pig but not human gallbladders contracted after stimulation with the alpha-adrenergic agonist phenylephrine. Erythromycin reduced these contractions in a concentration-dependent manner but had no effect on gallbladder contractions induced by bradykinin. In human gallbladder strips, erythromycin at 500 micromol/L reduced the contractile response to electrical stimulation to 71% +/- 16% of the control value (N = 10 [5 patients], P <0.01) and the carbachol-evoked contractions to 53% +/- 24% (P <0.01, N = 32). The inhibitory effect of erythromycin persisted in the presence of the nerve blocker tetrodotoxin at 1 micromol/L. It is concluded that erythromycin has a direct inhibitory effect on guinea pig and human gallbladder contractions.