Published online Mar 28, 2015. doi: 10.3748/wjg.v21.i12.3509
Peer-review started: October 6, 2014
First decision: October 29, 2014
Revised: November 6, 2014
Accepted: December 1, 2014
Article in press: December 1, 2014
Published online: March 28, 2015
AIM: To study the effects of entacapone, a catechol-O-methyltransferase inhibitor, on colon motility and electrolyte transport in Parkinson’s disease (PD) rats.
METHODS: Distribution and expression of catechol-O-methyltransferase (COMT) were measured by immunohistochemistry and Western blotting methods. The colonic smooth muscle motility was examined in vitro by means of a muscle motility recording device. The mucosal electrolyte transport of PD rats was examined by using a short-circuit current (ISC) technique and scanning ion-selective electrode technique (SIET). Intracellular detection of cAMP and cGMP was accomplished by radioimmunoassay testing.
RESULTS: COMT was expressed in the colons of both normal and PD rats, mainly on the apical membranes of villi and crypts in the colon. Compared to normal controls, PD rats expressed less COMT. The COMT inhibitor entacapone inhibited contraction of the PD rat longitudinal muscle in a dose-dependent manner. The β2 adrenoceptor antagonist ICI-118,551 blocked this inhibitory effect by approximately 67% (P < 0.01). Entacapone increased mucosal ISC in the colon of rats with PD. This induction was significantly inhibited by apical application of Cl- channel blocker diphenylamine-2, 2’-dicarboxylic acid, basolateral application of Na+-K+-2Cl-co-transporter antagonist bumetanide, elimination of Cl- from the extracellular fluid, as well as pretreatment using adenylate cyclase inhibitor MDL12330A. As an inhibitor of prostaglandin synthetase, indomethacin can inhibit entacapone-induced ISC by 45% (P < 0.01). When SIET was applied to measure Cl- flux changes, this provided similar results. Entacapone significantly increased intracellular cAMP content in the colonic mucosa, which was greatly inhibited by indomethacin.
CONCLUSION: COMT expression exists in rat colons. The β2 adrenoceptor is involved in the entacapone-induced inhibition of colon motility. Entacapone induces cAMP-dependent Cl- secretion in the PD rat.
Core tip: Entacapone, a catechol-O-methyltransferase (COMT) inhibitor, is an emerging drug for Parkinson’s disease (PD) patients. However, patients experience gastro-intestinal side effects with entacapone treatment and the reason for this is unknown. This study for the first time proved that COMT is expressed in normal and PD rat colons and that entacapone can inhibit PD rat muscle contraction through the β2 adrenoceptor. It was also discovered that entacapone can induce cAMP-dependent Cl- secretion in PD rats and that endogenous prostaglandin is involved in this process. These findings provided histological evidence of COMT in the colon, establishing an experimental basis for the mechanism of entacapone-induced PD gastro-intestinal side effects.