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The 5-HT4 receptor agonist prucalopride does not facilitate cholinergic neurotransmission in circular and longitudinal smooth muscle preparations of equine mid-jejunum

Romain Lefebvre (UGent) , Chana Callens (UGent) , Inge Van Colen (UGent) and Catherine Delesalle (UGent)
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Abstract
Background: Postoperative ileus (POI) remains an important cause of death in horses. The recently developed selective 5-HT4 receptor agonists such as prucalopride target 5-HT4 receptors on myenteric cholinergic neurons to enhance acetylcholine release and GI motility. No clearcut in vitro evaluation whether highly selective 5-HT4 receptor agonists enhance submaximal cholinergic neurotransmission towards the muscle layer has been performed in horses. Objectives: To identify functional 5-HT4 receptors in equine jejunum. Study design: In vitro experimental study. Methods: Circular and longitudinal smooth muscle strips (mid-jejunum) were mounted in organ baths between 2 platinum electrodes allowing electrical field stimulation (EFS). To delineate the conditions to obtain purely cholinergic responses, voltage-response curves were studied. To investigate the influence of prucalopride and 5 HT, submaximal cholinergic contractions at a single voltage were induced. Results: In circular and longitudinal strips, EFS induced voltage-dependent neurogenic on-contractions when the bathing medium contained a NO-synthesis inhibitor and apamin to prevent inhibitory responses to NO and ATP. Contractions at a voltage inducing 50% of maximal amplitude were cholinergic, as they were blocked by atropine. These contractions were not influenced by prucalopride (up to 3 mu M) even in the presence of the phosphodiesterase inhibitor isobutyl-methyl-xanthine to inhibit breakdown of the second messenger of 5-HT4 receptors, cAMP. Also the full 5-HT4 receptor agonist 5-HT did not influence the EFS-induced submaximal cholinergic contractions. Moreover, prucalopride did not influence muscle tone continuously enhanced with KCl. Conclusions: There are no functional 5-HT4 receptors on myenteric cholinergic neurons nor muscular 5-HT4 receptors in equine jejunum.
Keywords
Horse, Colic, Ileus, Small intestine, Gastroprokinetic, Neuronal 5-HT4 receptors, INHIBITORY NEUROMUSCULAR-TRANSMISSION, PIG DESCENDING COLON, IN-VITRO, PHARMACOLOGICAL CHARACTERIZATION, MECHANICAL MANIPULATIONS, GASTROINTESTINAL-TRACT, POSTOPERATIVE ILEUS, SMALL-INTESTINE, PELVIC FLEXURE, NITRIC-OXIDE

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Chicago
Lefebvre, Romain, Chana Callens, Inge Van Colen, and Catherine Delesalle. 2017. “The 5-HT4 Receptor Agonist Prucalopride Does Not Facilitate Cholinergic Neurotransmission in Circular and Longitudinal Smooth Muscle Preparations of Equine Mid-jejunum.” Research in Veterinary Science 114: 153–162.
APA
Lefebvre, R., Callens, C., Van Colen, I., & Delesalle, C. (2017). The 5-HT4 receptor agonist prucalopride does not facilitate cholinergic neurotransmission in circular and longitudinal smooth muscle preparations of equine mid-jejunum. RESEARCH IN VETERINARY SCIENCE, 114, 153–162.
Vancouver
1.
Lefebvre R, Callens C, Van Colen I, Delesalle C. The 5-HT4 receptor agonist prucalopride does not facilitate cholinergic neurotransmission in circular and longitudinal smooth muscle preparations of equine mid-jejunum. RESEARCH IN VETERINARY SCIENCE. 2017;114:153–62.
MLA
Lefebvre, Romain, Chana Callens, Inge Van Colen, et al. “The 5-HT4 Receptor Agonist Prucalopride Does Not Facilitate Cholinergic Neurotransmission in Circular and Longitudinal Smooth Muscle Preparations of Equine Mid-jejunum.” RESEARCH IN VETERINARY SCIENCE 114 (2017): 153–162. Print.
@article{8522731,
  abstract     = {Background: Postoperative ileus (POI) remains an important cause of death in horses. The recently developed selective 5-HT4 receptor agonists such as prucalopride target 5-HT4 receptors on myenteric cholinergic neurons to enhance acetylcholine release and GI motility. No clearcut in vitro evaluation whether highly selective 5-HT4 receptor agonists enhance submaximal cholinergic neurotransmission towards the muscle layer has been performed in horses. 
Objectives: To identify functional 5-HT4 receptors in equine jejunum. 
Study design: In vitro experimental study. 
Methods: Circular and longitudinal smooth muscle strips (mid-jejunum) were mounted in organ baths between 2 platinum electrodes allowing electrical field stimulation (EFS). To delineate the conditions to obtain purely cholinergic responses, voltage-response curves were studied. To investigate the influence of prucalopride and 5 HT, submaximal cholinergic contractions at a single voltage were induced. 
Results: In circular and longitudinal strips, EFS induced voltage-dependent neurogenic on-contractions when the bathing medium contained a NO-synthesis inhibitor and apamin to prevent inhibitory responses to NO and ATP. Contractions at a voltage inducing 50\% of maximal amplitude were cholinergic, as they were blocked by atropine. These contractions were not influenced by prucalopride (up to 3 mu M) even in the presence of the phosphodiesterase inhibitor isobutyl-methyl-xanthine to inhibit breakdown of the second messenger of 5-HT4 receptors, cAMP. Also the full 5-HT4 receptor agonist 5-HT did not influence the EFS-induced submaximal cholinergic contractions. Moreover, prucalopride did not influence muscle tone continuously enhanced with KCl. 
Conclusions: There are no functional 5-HT4 receptors on myenteric cholinergic neurons nor muscular 5-HT4 receptors in equine jejunum.},
  author       = {Lefebvre, Romain and Callens, Chana and Van Colen, Inge and Delesalle, Catherine},
  issn         = {0034-5288},
  journal      = {RESEARCH IN VETERINARY SCIENCE},
  keyword      = {Horse,Colic,Ileus,Small intestine,Gastroprokinetic,Neuronal 5-HT4 receptors,INHIBITORY NEUROMUSCULAR-TRANSMISSION,PIG DESCENDING COLON,IN-VITRO,PHARMACOLOGICAL CHARACTERIZATION,MECHANICAL MANIPULATIONS,GASTROINTESTINAL-TRACT,POSTOPERATIVE ILEUS,SMALL-INTESTINE,PELVIC FLEXURE,NITRIC-OXIDE},
  language     = {eng},
  pages        = {153--162},
  title        = {The 5-HT4 receptor agonist prucalopride does not facilitate cholinergic neurotransmission in circular and longitudinal smooth muscle preparations of equine mid-jejunum},
  url          = {http://dx.doi.org/10.1016/j.rvsc.2017.04.006},
  volume       = {114},
  year         = {2017},
}

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