Enteric locus of action of prokinetics: ABT-229, motilin, and erythromycin

We investigated the in vivo and in vitro locus of actions of prokinetics: m otilin, erythromycin, and ABT-229. The test substances were infused close i ntra-arterially in short segments of the jejunum in the intact conscious st ate. Each prokinetic acted on a presynaptic neuron and utilized at least on e nicotinic synapse to stimulate circular muscle contractions. The final ne urotransmitter at the neuroeffector junction was ACh. Motilin and erythromy cin, but not ABT-229, also released nitric oxide. Each prokinetic utilized somewhat different subtypes of muscarinic, serotonergic, tachykininergic, a nd histaminergic receptors, except for the Mg 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 meth acholine or electrical field stimulation induced phasic contractions in all of them. The prokinetics also did not release ACh in longitudinal muscle-m yenteric plexus preparations. Each prokinetic, however, decreased the lengt h of enzymatically dispersed single cells. In conclusion, each prokinetic m ay act on a different subset of presynaptic neurons that converge on the po stsynaptic cholinergic and nonadrenergic noncholinergic motoneurons. The pr esynaptic neurons may be impaired in the muscle bath environment.