恩他卡朋促进大鼠cAMP依赖的Cl分泌引起胃肠不适 分析测试百科网...

恩他卡朋（Entacapone）是一种广泛用于帕金森疾病（PD）治疗的药物，是儿茶酚-O-甲基转移酶（COMT）的抑制剂。然而，恩他卡朋有胃肠副作用，临床上约10%的服用者会出现腹泻。为了研究产生腹泻的机理，科学家采用的新方法非损伤微测技术结合传统方法研究了恩他卡朋造成腹泻的原因。

2011年，首都医科大学的朱进霞实验室使用非损伤微测技术测定了Cl-的流速，短路电流（ISC）测定了带电的离子运输，放射性免疫方法（RIA）测定了胞内的cAMP含量。发现恩他卡朋增加了大鼠末梢结肠粘膜的ISC和Cl-分泌，顶端施加二苯胺2，2’-二羧酸（DPC）（一种Cl-通道抑制剂）显著抑制了ISC，基底外侧施用布美他尼（Na+-K+-2Cl-（NLCC）共转运抑制剂）等显著抑制了Cl-外流。消炎痛抑制内源前列腺素（PG）的合成，并且降低了粘膜下层肠神经的活性以及河豚毒素（TTX）抑制的恩他卡朋引起的ISC的增加和Cl-的分泌。

恩他卡朋刺激大鼠结肠cAMP依赖的Cl-的分泌，这个过程由内源的PG和粘膜下层肠神经系统所调节。这项研究比较完善地解释了恩他卡朋产生胃肠道不适应症的原因，即Cl-大量分泌。

关键词：恩他卡朋（Entacapone），离子分泌，非损伤微测技术，短路电流

参考文献：Li LS, et al. Neurogastroenterology and Motility, 2011, 23(7): 657-e277.

Entacaponepromotes cAMP-dependent colonic Cl-secretion in rats 恩他卡朋促进大鼠结肠中cAMP依赖型Cl-分泌

Abstract
Background Entacapone is a promising drug used widely for the treatment ofParkinson’s disease (PD) as a catechol-O-methyl transferase (COMT) inhibitor.However, entacapone has gastrointestinal side effects.The aim of thisstudy was to investigate the effects of entacapone on the epithelial iontransport in rat distal colon, and explore the underlying mechanism.
Methods Thestudy was performed on freshly isolated colonic mucosa-only, submucosa-only andmucosa–submucosa preparations in rat. The short circuit current (ISC) wasmeasured to determine electrogenic ion transport, and a scanning ion-selectiveelectrode technique (SIET) was used to directly measure Cl- flux across the epithelium. The content of intracellular cAMP was measured with radioimmunoassay (RIA).
Key Results Entacaponeincreased mucosal ISC in the rat distal colon. ISC was inhibited significantlyby apical addition of diphenylamine-2,2’-dicarboxylic acid(DPC), a blocker of the Cl- channel, basolateral applicationof bumetanide, an inhibitor of Na+-K+-2Cl- co-transporter (NKCC), emoval of Cl- from the bathingsolution, and pretreatment with MDL 12330A, an inhibitor of adenylate cyclase.Inhibiting endogenous prostaglandin (PG) synthesis with indomethacin,andeliminating submucosal enteric neural activity with tetrodotoxin(TTX)-inhibited entacapone- evoked ISC increases. Similar results were also obtainedwhen Cl- flux was measured with SIET.Entacaponesignificantly increased intracellular cAMP content, which was greatly inhibitedby either indomethacin or TTX in the tissues containing submucosal plexus, andby only indomethacin in the mucosa-only preparations.
Conclusions Inferences Entacapone stimulates cAMP-dependent Cl- secretionin the rat colon,and this process is regulated by endogenous PG and thesubmucosal enteric nervous system.