Department of Urology, Ankara Numune Education and Research Hospital, Ankara, Turkey.
Urology. 2011 Oct;78(4):968.e1-6. doi: 10.1016/j.urology.2011.06.033. Epub 2011 Aug 27.
To evaluate the mechanism of action of imatinib mesylate (Gleevec), a protein tyrosine kinase inhibitor on the human prostate with benign prostatic hyperplasia.
Prostate samples were obtained from 16 patients with benign prostatic hyperplasia (mean age 68.3 ± 1.9 years), who had undergone transurethral prostatectomy. In tissue bath studies, cumulative concentration-response curves were constructed for imatinib after precontraction with 120 mM KCl. Imatinib-induced relaxation was quantitated in tissues treated with l-N(G)-Nitroarginine Methyl Ester (l-NAME) (an inhibitor of nitric oxide synthase) or 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (a soluble guanylyl cyclase inhibitor). Two K+ channel blockers (adenosine triphosphate [K(ATP)] and Large-conductance Ca(2+)-activated K(+) channels [BK(Ca2+)] channels) were also evaluated as antagonists of imatinib-induced relaxation and repeated in the presence of the α-adrenergic receptor blocker alfuzosin. An electrical field stimulation (1-20 Hz, 5 ms, 5 seconds, 60 V)-induced contractile response was performed on strips incubated with imatinib (10(-3) M).
KCl-induced contractions in human prostatic tissue were significantly inhibited by imatinib (maximal response 84.9 ± 4.5%) and were attenuated by l-NAME (42%, P < .001) and ODQ (43%, P < .001). This relaxant effect was also suppressed by glibenclamide (adenosine triphosphate-sensitive K+ channel blocker, 41%, P < .001) and tetraethylammonium (BK(Ca2+) channel blocker, 24%, P < .05).
Imatinib induced prostatic smooth muscle relaxation in vitro. This effect was suppressed by l-NAME and ODQ, showing a dependence on the nitric oxide-cyclic guanosine monophosphate pathway and modulated by the K(ATP) and BK(Ca2+) K+ channels. Our findings suggest that imatinib can augment relaxation of human prostatic tissues by way of a novel ligand-protein tyrosine kinase signaling pathway.
评估甲磺酸伊马替尼（格列卫）作为一种蛋白酪氨酸激酶抑制剂对人前列腺良性前列腺增生的作用机制。
从 16 名接受经尿道前列腺切除术的良性前列腺增生患者（平均年龄 68.3±1.9 岁）的前列腺组织中获得样本。在组织浴研究中，通过用 120mM KCl 预收缩构建累积浓度-反应曲线。用 l-N（G）-硝基精氨酸甲酯（l-NAME）（一氧化氮合酶抑制剂）或 1H-[1,2,4]-恶二唑并[4,3-a]喹喔啉-1-酮（ODQ）（可溶性鸟苷酸环化酶抑制剂）处理组织，定量测定伊马替尼诱导的松弛。还评估了两种钾通道阻滞剂（三磷酸腺苷[K（ATP）]和大电导钙激活钾[BK（Ca2+）]通道）作为伊马替尼诱导松弛的拮抗剂，并在 α-肾上腺素能受体阻滞剂阿夫唑嗪存在下重复。对用伊马替尼（10（-3）M）孵育的条带进行电刺激（1-20Hz，5ms，5 秒，60V）诱导的收缩反应。
伊马替尼显著抑制人前列腺组织中 KCl 诱导的收缩（最大反应 84.9±4.5%），并被 l-NAME（42%，P<0.001）和 ODQ（43%，P<0.001）减弱。这种松弛作用也被格列本脲（三磷酸腺苷敏感钾通道阻滞剂，41%，P<0.001）和四乙铵（BK（Ca2+）通道阻滞剂，24%，P<0.05）抑制。
伊马替尼在体外诱导前列腺平滑肌松弛。这种作用被 l-NAME 和 ODQ 抑制，表明其依赖于一氧化氮-环鸟苷酸途径，并受 K（ATP）和 BK（Ca2+）K+通道调节。我们的发现表明，伊马替尼可以通过一种新的配体-蛋白酪氨酸激酶信号通路增强人前列腺组织的松弛。
