Effects of imatinib mesylate on spontaneous electrical and mechanical activity in smooth muscle of the guinea-pig stomach
Effects of imatinib mesylate on spontaneous electrical and mechanical activity in smooth muscle of the guinea-pig stomach
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DOI：
10.1038/bjp.2008.91
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发表时间：
2008-05-01
影响因子：
7.3
通讯作者：
Suzuki, H.
中科院分区：
文献类型：
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作者：
Hashitani, H.;Hayase, M.;Suzuki, H.
背景与目的：研究Kit受体酪氨酸激酶抑制剂甲磺酸伊马替尼对Cajal间质细胞（ICC）和胃平滑肌自发活动的影响。实验方法：通过测量豚鼠胃平滑肌记录的膜电位和张力的变化，研究伊马替尼对自发电和机械活动的影响。还在加载 fura-2 的制剂中检查了其对细胞内 Ca(2+) 浓度自发变化（[Ca(2+)](i)）（Ca(2+) 瞬变）的影响。主要结果：伊马替尼 (1-10 μM) 抑制自发收缩和 Ca(2+) 瞬变。电和机械活动的同时记录表明，伊马替尼 (1 μM) 降低了自发收缩的幅度，而不抑制相应的慢波。在硝苯地平（1μM）存在下，伊马替尼（10μM）减少了慢波和窦部随动电位的持续时间，并加速了它们的产生，但对其幅度影响不大。相反，伊马替尼降低了胃窦慢电位和胃体慢波的幅度。结论和意义：伊马替尼可能通过抑制平滑肌中增加[Ca(2+)](i)的途径而不是特异性抑制ICC的活性来抑制胃平滑肌的自发收缩。高浓度的伊马替尼（10μM）减少了胃窦慢波或跟随电位的持续时间，反映了分布在肌间层（ICC-MY）的ICC活性，并抑制了胃窦慢电位或下体慢波，反映了肌束内ICC的活动（ICC-IM），可能是通过抑制细胞内Ca（2+）处理。
Background and purpose: Effects of imatinib mesylate, a Kit receptor tyrosine kinase inhibitor, on spontaneous activity of interstitial cells of Cajal (ICC) and smooth muscles in the stomach were investigated.Experimental approach: Effects of imatinib on spontaneous electrical and mechanical activity were investigated by measuring changes in the membrane potential and tension recorded from smooth muscles of the guinea-pig stomach. Its effects on spontaneous changes in intracellular concentration of Ca(2+) ([Ca(2+)](i)) (Ca(2+) transients) were also examined in fura-2-loaded preparations.Key results: Imatinib (1-10 mu M) suppressed spontaneous contractions and Ca(2+) transients. Simultaneous recordings of electrical and mechanical activity demonstrated that imatinib (1 mu M) reduced the amplitude of spontaneous contractions without suppressing corresponding slow waves. In the presence of nifedipine (1 mu M), imatinib (10 mu M) reduced the duration of slow waves and follower potentials in the antrum and accelerated their generation, but had little affect on their amplitude. In contrast, imatinib reduced the amplitude of antral slow potentials and slow waves in the corpus.Conclusions and implications: Imatinib may suppress spontaneous contractions of gastric smooth muscles by inhibiting pathways that increase [Ca(2+)](i) in smooth muscles rather than by specifically inhibiting the activity of ICC. A high concentration of imatinib (10 mu M) reduced the duration of slow waves or follower potentials in the antrum, which reflect activity of ICC distributed in the myenteric layers (ICC-MY), and suppressed antral slow potentials or corporal slow waves, which reflect activity of ICC within the muscle bundles (ICC-IM), presumably by inhibiting intracellular Ca(2+) handling.