恩他卡朋促進(jìn)大鼠cAMP-依賴的Cl-分泌引起胃腸不適

      恩他卡朋（Entacapone）是一種廣泛用于帕金森疾�。�PD）治療的藥物，是兒茶酚-O-甲基轉(zhuǎn)移酶（COMT）的抑制劑。然而，恩他卡朋有胃腸副作用，臨床上約10%的服用者會(huì)出現(xiàn)腹瀉。為了研究產(chǎn)生腹瀉的機(jī)理，科學(xué)家采用的新方法非損傷微測(cè)技術(shù)結(jié)合傳統(tǒng)方法研究了恩他卡朋造成腹瀉的原因。

      2011年，首都醫(yī)科大學(xué)的朱進(jìn)霞實(shí)驗(yàn)室使用非損傷微測(cè)技術(shù)測(cè)定了Cl^-的流速，短路電流（ISC）測(cè)定了帶電的離子運(yùn)輸，放射性免疫方法（RIA）測(cè)定了胞內(nèi)的cAMP含量。發(fā)現(xiàn)恩他卡朋增加了大鼠末梢結(jié)腸粘膜的ISC和Cl^-分泌，頂端施加二苯胺2，2’-二羧酸（DPC）（一種Cl-通道抑制劑）顯著抑制了ISC，基底外側(cè)施用布美他尼（Na⁺-K⁺-2Cl^-（NLCC）共轉(zhuǎn)運(yùn)抑制劑）等顯著抑制了Cl^-外流。消炎痛抑制內(nèi)源前列腺素（PG）的合成，并且降低了粘膜下層腸神經(jīng)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。

      恩他卡朋刺激大鼠結(jié)腸cAMP依賴的Cl-的分泌，這個(gè)過程由內(nèi)源的PG和粘膜下層腸神經(jīng)系統(tǒng)所調(diào)節(jié)。這項(xiàng)研究比較完善地解釋了恩他卡朋產(chǎn)生胃腸道不適應(yīng)癥的原因，即Cl^-大量分泌。

關(guān)鍵詞：恩他卡朋（Entacapone），離子分泌，非損傷微測(cè)技術(shù)，短路電流

參考文獻(xiàn)：Li LS, et al. Neurogastroenterology and Motility, 2011, 23(7): 657-e277.

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Entacaponepromotes cAMP-dependent colonic Cl-secretion in rats 恩他卡朋促進(jìn)大鼠結(jié)腸中cAMP依賴型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 (I_SC) 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 I_SC in the rat distal colon. I_SC 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 I_SC 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.