Enteric locus of action of prokinetics: ABT-229, motilin, and erythromycin.
We investigated the in vivo and in vitro locus of actions of prokinetics: motilin, erythromycin, and ABT-229. The test substances were infused close intra-arterially in short segments of the jejunum in the intact conscious state. Each prokinetic acted on a presynaptic neuron and utilized at least one nicotinic synapse to stimulate circular muscle contractions. The final neurotransmitter at the neuroeffector junction was ACh. Motilin and erythromycin, but not ABT-229, also released nitric oxide. Each prokinetic utilized somewhat different subtypes of muscarinic, serotonergic, tachykininergic, and histaminergic receptors, except for the M(3) receptor, which was common to all of them. In contrast, none of the prokinetics stimulated contractions in mucosa-free or mucosa-attached muscle strips, or rings, even though methacholine or electrical field stimulation induced phasic contractions in all of them. The prokinetics also did not release ACh in longitudinal muscle-myenteric plexus preparations. Each prokinetic, however, decreased the length of enzymatically dispersed single cells. In conclusion, each prokinetic may act on a different subset of presynaptic neurons that converge on the postsynaptic cholinergic and nonadrenergic noncholinergic motoneurons. The presynaptic neurons may be impaired in the muscle bath environment.
Sarna
S K
SK
Departments of Surgery and Physiology, Medical College of Wisconsin, and Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin 53226, USA. ssarna@mcw.edu
Gonzalez
A
A
Ryan
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RP
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D004285:Dogs; D004386:Duodenum / Q000187:drug effects / Q000502:physiology*; D004558:Electric Stimulation; D004917:Erythromycin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005260:Female; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D005769:Gastrointestinal Motility / Q000187:drug effects*; D018738:Hexamethonium / Q000494:pharmacology; D066298:In Vitro Techniques; D007261:Infusions, Intra-Arterial; D007413:Intestinal Mucosa / Q000502:physiology; D007583:Jejunum / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D009037:Motilin / Q000008:administration & dosage / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D011817:Rabbits; D013270:Stomach / Q000187:drug effects / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology
D005765:Gastrointestinal Agents; D016210:Methacholine Chloride; D018738:Hexamethonium; D013779:Tetrodotoxin; D009037:Motilin; C114264:Alemcinal; D004917:Erythromycin; D001285:Atropine; D019331:NG-Nitroarginine Methyl Ester