Concentration-dependent stimulation of cholinergic motor nerves or smooth muscle by [Nle13]motilin in the isolated rabbit gastric antrum.
In man, rabbit and cat, the effects of motilin and motilides are neurally mediated in vivo, whereas in vitro binding and contractility studies suggest the presence of a smooth muscular receptor. The aim of this study was to investigate in vitro interactions of motilin with the enteric excitatory neurotransmission in the gastric antrum of the rabbit. Circular muscle strips from the pre-pyloric antrum were subjected to electrical field stimulation (1 ms, 1-32 Hz, 10 s train) and muscle twitch responses were recorded isometrically. Induced twitch responses were frequency dependent (1-32 Hz) and entirely neurogenic (tetrodotoxin sensitive). [Nle13]motilin dose-dependently (10[-9]-10[-8] M) enhanced the amplitude of, atropine sensitive, evoked contractions. At 4 Hz the response, expressed as a % of the response to 32 Hz, increased from 15.5 +/- 4.1% (control) to 28.1 +/- 5.8% (motilin 10[-9] M), and to 45.8 +/- 3.6% (motilin 10[-8.5] M) (P < 0.05). This effect was not inhibited by hexamethonium (10[-3.3] M) but was abolished by the motilin receptor antagonist GM-109 (10[-5] M). In unstimulated strips, motilin induced phasic-tonic contractions with a threshold concentration of 10[-8] M and an pEC50 of 7.48, which were also inhibited by GM-109 (10[-5] M) but not by tetrodotoxin (10[-5.5] M). The maximal tension, frequency and dose-dependency of carbachol-induced contractions were not influenced by motilin (pEC50, carbachol: 6.48 +/- 0.06 (control), 6.49 +/- 0.07 (motilin)). In conclusion, motilin enhances contractions induced by electrical field stimulation in the rabbit antrum by a post-ganglionic interaction with the cholinergic neurotransmission in vitro at low doses and interacts directly with antral smooth muscle at high doses. This model is an accurate reflection of the in vivo effects of motilin and provides a tool to study neurogenic and myogenic actions of motilin and motilides in vitro.
Van Assche
G
G
Department of Pathophysiology, University of Leuven, Belgium.
Depoortere
I
I
Thijs
T
T
Janssens
J J
JJ
Peeters
T L
TL
D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D017615:Enteric Nervous System / Q000187:drug effects* / Q000502:physiology; D005260:Female; D005730:Ganglionic Blockers / Q000494:pharmacology; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D018738:Hexamethonium / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009037:Motilin / Q000031:analogs & derivatives* / Q000494:pharmacology; D009046:Motor Neurons / Q000187:drug effects* / Q000502:physiology; D018721:Muscarinic Agonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000294:innervation / Q000502:physiology; D011706:Pyloric Antrum / Q000187:drug effects* / Q000294:innervation / Q000502:physiology; D011817:Rabbits; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D005730:Ganglionic Blockers; D005765:Gastrointestinal Agents; D018721:Muscarinic Agonists; D018738:Hexamethonium; D009037:Motilin; C013087:13-Leu-motilin; D002217:Carbachol