title: Entacapone promotes cAMP-dependent colonic Cl(-) secretion in rats.
abstract: BACKGROUND
  Entacapone is a promising drug used widely for the treatment of Parkinson's disease (PD) as a catechol-O-methyl transferase (COMT) inhibitor. However, entacapone has gastrointestinal side effects. The aim of this study was to investigate the effects of entacapone on the epithelial ion transport in rat distal colon, and explore the underlying mechanism.
  
  
  METHODS
  The study was performed on freshly isolated colonic mucosa-only, submucosa-only and mucosa-submucosa preparations in rat. The short circuit current (I(SC) ) was measured to determine electrogenic ion transport, and a scanning ion-selective electrode technique (SIET) was used to directly measure Cl(-) flux across the epithelium. The content of intracellular cAMP was measured with radioimmunoassay (RIA).
  
  
  RESULTS
  Entacapone increased mucosal I(SC) in the rat distal colon. I(SC) was inhibited significantly by apical addition of diphenylamine-2,2'-dicarboxylic acid (DPC), a blocker of the Cl(-) channel, basolateral application of bumetanide, an inhibitor of Na(+) -K(+) -2Cl(-) co-transporter (NKCC), removal of Cl(-) from the bathing solution, and pretreatment with MDL 12330A, an inhibitor of adenylate cyclase. Inhibiting endogenous prostaglandin (PG) synthesis with indomethacin, and eliminating submucosal enteric neural activity with tetrodotoxin (TTX)-inhibited entacapone-evoked I(SC) increases. Similar results were also obtained when Cl(-) flux was measured with SIET. Entacapone significantly increased intracellular cAMP content, which was greatly inhibited by either indomethacin or TTX in the tissues containing submucosal plexus, and by only indomethacin in the mucosa-only preparations.
  
  
  CONCLUSIONS
  Entacapone stimulates cAMP-dependent Cl(-) secretion in the rat colon, and this process is regulated by endogenous PG and the submucosal enteric nervous system.
authors.affiliation: Department of Physiology School of Basic Medical Sciences, Capital Medical University, Beijing, China.
authors.forename: L-S
authors.initials: LS
authors.lastname: Li
authors.forename: L-F
authors.initials: LF
authors.lastname: Zheng
authors.forename: J-D
authors.initials: JD
authors.lastname: Xu
authors.forename: T
authors.initials: T
authors.lastname: Ji
authors.forename: H
authors.initials: H
authors.lastname: Guo
authors.forename: X-F
authors.initials: XF
authors.lastname: Li
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: J-X
authors.initials: JX
authors.lastname: Zhu
mesh_terms: D000818:Animals; D002396:Catechols / Q000494:pharmacology*; D018118:Chloride Channels / Q000187:drug effects; D002712:Chlorides / Q000378:metabolism*; D003106:Colon / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D017615:Enteric Nervous System / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000378:metabolism; D017136:Ion Transport / Q000187:drug effects; D008297:Male; D023421:Models, Animal; D009570:Nitriles / Q000494:pharmacology*; D011453:Prostaglandins / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology
chemical_list: D002396:Catechols; D018118:Chloride Channels; D002712:Chlorides; D004791:Enzyme Inhibitors; D009570:Nitriles; D011453:Prostaglandins; D049994:Sodium Potassium Chloride Symporter Inhibitors; C071192:entacapone; D000242:Cyclic AMP