Department of Urology, Tulane Health Sciences Center, New Orleans, LA, USA.
Urology. 2013 Sep;82(3):745.e11-6. doi: 10.1016/j.urology.2013.04.030. Epub 2013 Jul 13.
To evaluate the effect of the tyrosine kinase inhibitor imatinib mesylate (Gleevec) on human corpus cavernosum (HCC) smooth muscle tone.
HCC were obtained from 18 erectile dysfunction (ED) patients undergoing penile prosthesis surgery. The effects of imatinib in HCC strips were investigated in the presence of various inhibitors. The human phosphoreceptor protein tyrosine kinase (PTK) array (Proteome Profiler Array) detected changes in receptor phosphorylation before and after imatinib. Immunohistochemistry was used to localize phosphorylated c-kit (CD117/stem cell factor) in HCC smooth muscle cells.
Phenylephrine-induced contraction in HCC was significantly inhibited by imatinib (97.7% ± 2.3%). l-nitro-arginine methyl ester (l-NAME) or guanylyl cyclase inhibitor [1H-1,2,4] oxadiazolo [4,3-a]quinoxalin-1-one (ODQ) alone did not reverse the effect of imatinib, but suppressed this response in combination (18.0% ± 0.6%). The K(+) channel blockers (apamin and tetraethyl ammonium) decreased the imatinib-induced relaxation by 64% and 51%, respectively. PTK microarray analysis of 42 different phospho-receptor tyrosine kinases showed 14 were clearly activated in HCC. Imatinib treatment significantly inhibited phosphorylation of PTKs. A high level of CD117/c-kit-positive immunostaining was detected in untreated HCC smooth muscle, but not in treated HCC.
Imatinib caused HCC smooth muscle relaxation in vitro mediated by nitric oxide/guanosine monophosphate signaling, involving the large-conductance Ca(2+)-activated K(+)-channels (BK(Ca)) or by inhibiting the upregulated PTK pathway. These results suggest that imatinib may also benefit erectile dysfunction patients who are not responsive to phosphodiesterase-5 inhibitors.
评估甲磺酸伊马替尼（格列卫）对人阴茎海绵体（HCC）平滑肌张力的影响。
从 18 名接受阴茎假体手术的勃起功能障碍（ED）患者中获得 HCC。在存在各种抑制剂的情况下，研究了伊马替尼对 HCC 条带的影响。人类磷酸受体蛋白酪氨酸激酶（PTK）阵列（Proteome Profiler Array）检测了伊马替尼前后受体磷酸化的变化。免疫组织化学用于定位 HCC 平滑肌细胞中磷酸化的 c-kit（CD117/干细胞因子）。
伊马替尼显著抑制了 HCC 引起的去甲肾上腺素诱导的收缩（97.7%±2.3%）。l-硝基-精氨酸甲酯（l-NAME）或鸟苷酸环化酶抑制剂[1H-1,2,4]恶二唑[4,3-a]喹喔啉-1-酮（ODQ）单独使用不能逆转伊马替尼的作用，但联合使用时抑制了这种反应（18.0%±0.6%）。K+通道阻滞剂（apamin 和四乙铵）分别使伊马替尼诱导的松弛减少了 64%和 51%。42 种不同磷酸化受体酪氨酸激酶的 PTK 微阵列分析显示，14 种在 HCC 中明显被激活。伊马替尼处理显著抑制了 PTK 的磷酸化。在未处理的 HCC 平滑肌中检测到高水平的 CD117/c-kit 阳性免疫染色，但在处理过的 HCC 中未检测到。
伊马替尼在体外引起 HCC 平滑肌松弛，由一氧化氮/鸟苷酸单磷酸信号介导，涉及大电导钙激活钾通道（BK（Ca））或通过抑制上调的 PTK 途径。这些结果表明，伊马替尼也可能有益于对磷酸二酯酶-5 抑制剂无反应的勃起功能障碍患者。
