Erythromycin stimulates ileal motility by activation of dihydropyridine-sensitive calcium channels.
Erythromycin, a macrolide antibiotic, is a potent stimulant of small bowel motor activity (MA) which may motility either via the peptide motilin receptor or neural mechanisms. We hypothesized that erythromycin stimulates directly stimulates smooth muscle cells by a calcium-mediated event. Thus, we evaluated the effect of neuronal blockade with tetrodotoxin, muscarinic blockade with atropine, and opiate blockade with naloxone on erythromycin-stimulated MA in isolated perfused segments of rabbit terminal ileum. We also tested the effect of nonspecific calcium channel blockade (verapamil and cadmiun) and specific blockade (dihydroxypyridine and nichol) on erythromycin-stimulated MA. MA was measured with a multichannel continuous perfusion manometry catheter. Erythromycin caused a concentration-dependent increase in MA (ED100 5 x 10(-4) M). Tetrodotoxin, atropine, and naloxone did not effect erythromycin-stimulated MA (P greater than 0.05). Both verapamil (10(-7) M) and cadmium (10(-2)-10(-4) M) inhibited erythromycin-stimulated MA. Selective blockade of "l" type calcium channels using dihydropyridine (10(-6) M) and "t" channels with nickel (10(-2)-10(-4) M) both reversed erythromycin-stimulated MA. Since the isolated segments of terminal ileum were free of exogenous humoral and neural effects, these studies indicated that erythromycin directly stimulated MA in the terminal ileum. Furthermore, since tetrodotoxin, atropine, and naloxone did not inhibit this increase in MA, erythromycin acted by a mechanism which was independent of the intrinsic nervous and opiate systems. In conclusion, these data are consistent with the model that erythromycin stimulates ileal motility by a mechanism involving activation of dihydroxypyridine and nickel-sensitive calcium channels.
Armstrong
D N
DN
Department of Surgery, Yale University School of Medicine, West Haven V.A. Medical Center, Connecticut 06510.
Ballantyne
G H
GH
Modlin
I M
IM
D000818:Animals; D001784:Blood Gas Analysis; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects*; D004095:Dihydropyridines / Q000494:pharmacology*; D004917:Erythromycin / Q000494:pharmacology*; D005769:Gastrointestinal Motility / Q000187:drug effects*; D007082:Ileum / Q000502:physiology*; D015640:Ion Channel Gating / Q000187:drug effects; D011817:Rabbits
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; D004917:Erythromycin; C038806:1,4-dihydropyridine