Entacapone promotes cAMP-dependent colonic Cl secretion in rats

Authors


Address for Correspondence
Jin-Xia Zhu, Department of Physiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
Tel: +86 10 8391 1494; fax: +86 10 8391 1494;
e-mail: zhu_jx@ccmu.edu.cn

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 (ISC) 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).

Key Results  Entacapone increased mucosal ISC in the rat distal colon. ISC 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 ISC 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 & Inferences  Entacapone stimulates cAMP-dependent Cl secretion in the rat colon, and this process is regulated by endogenous PG and the submucosal enteric nervous system.

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