Effects of imatinib mesylate (Glivec®) as a c-kit tyrosine kinase inhibitor in the guinea-pig urinary bladder
Effects of imatinib mesylate (Glivec®) as a c-kit tyrosine kinase inhibitor in the guinea-pig urinary bladder
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DOI：
10.1002/nau.20085
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发表时间：
2006-01-01
影响因子：
2
通讯作者：
Brading, AF
中科院分区：
文献类型：
--
作者：
Kubota, Y;Biers, SM;Brading, AF
在胃肠道中，平滑肌中的慢波活动由Cajal间质细胞（ICC）产生。大多数物种的逼尿肌平滑肌条显示由动作电位爆发触发的自发收缩，然而，逼尿肌的起搏机制仍然未知。最近，利用c-kit受体的抗体，在豚鼠膀胱中发现了ICC样细胞。我们研究了一种c-kit酪氨酸激酶抑制剂Glivec对豚鼠逼尿肌自发动作电位和离体豚鼠膀胱内压的影响。方法：采用传统的微电极技术测定豚鼠逼尿肌平滑肌膜电位的变化。使用全器官浴技术记录膀胱中的压力变化。结果如下：逼尿肌束平滑肌细胞出现自发性动作电位，离体膀胱出现自发性压力升高。Glivec（10 μ M）将动作电位爆发转换为连续放电，对单个动作电位的形状没有影响。格列卫（> 50 μ M）以剂量依赖性方式降低整个膀胱中自发性压力升高的幅度，并消除逼尿肌平滑肌细胞中的自发性动作电位。结论：结果表明，ICC样细胞可能负责产生动作电位和逼尿肌收缩的爆发。抑制c-kit受体的药物可能被证明对治疗膀胱过度活动症有用。
In the gastrointestinal tract, slow wave activity in smooth muscle is generated by the interstitial cells of Cajal (ICC). Detrusor smooth muscle strips of most species show spontaneous contractions which are triggered by action potential bursts, however, the pacemaker mechanisms for the detrusor are still unknown. Recently, ICC-like cells have been found in guinea-pig bladder, using antibodies to the c-kit receptor. We have investigated the effects of Glivec, a c-kit tyrosine kinase inhibitor, on spontaneous action potentials in guinea-pig detrusor and intravesical pressure of isolated guinea-pig bladders. Methods: Changes in the membrane potential were measured in guinea-pig detrusor smooth muscle using conventional microelectrode techniques. Pressure changes in the bladder were recorded using whole organ bath techniques. Results: Smooth muscle cells in detrusor muscle bundles exhibited spontaneous action potentials, and spontaneous pressure rises occurred in isolated bladders. Glivec (10 mu M) converted action potential bursts into continuous firing with no effects on the shape of individual action potentials. Glivec (> 50 mu M) reduced the amplitude of spontaneous pressure rises in the whole bladder in a dose dependent manner and abolished spontaneous action potentials in detrusor smooth muscle cells. Conclusions: The results suggest that ICC-like cells may be responsible for generating bursts of action potentials and contractions in detrusor smooth muscle. Drugs inhibiting the c-kit receptor may prove useful for treating the over-active bladder.