Tyrosine Kinase Inhibitors Are Potent Acute Pulmonary Vasodilators in Rats
Tyrosine Kinase Inhibitors Are Potent Acute Pulmonary Vasodilators in Rats
复制标题
DOI：
10.1165/rcmb.2010-0371oc
复制
发表时间：
2011-10-01
影响因子：
6.4
通讯作者：
Oka, Masahiko
中科院分区：
文献类型：
--
作者：
Abe, Kohtaro;Toba, Michie;Oka, Masahiko
酪氨酸激酶抑制剂有望用于治疗重度肺动脉高压。它们的治疗作用被假定是由于抑制细胞生长相关激酶和减弱血管重塑。其潜在的血管舒张活性尚未探索。酪氨酸激酶抑制剂伊马替尼，索拉非尼，尼洛替尼的血管舒张作用进行了检查，在正常和肺动脉高压大鼠离体肺动脉环。通过蛋白质印迹法评估肌球蛋白轻链磷酸酶和肌球蛋白轻链的磷酸化。在肺动脉高压大鼠中检测伊马替尼的急性血流动力学效应。在正常肺动脉中，伊马替尼以浓度依赖性和内皮非依赖性方式逆转了降钙素和U46619诱导的收缩。索拉非尼和尼洛替尼缓解U46619诱导的收缩。伊马替尼抑制U46619诱导的正常肺动脉肌球蛋白磷酸酶的活化。所有三种酪氨酸激酶抑制剂浓度依赖性和完全逆转自发性收缩的高血压肺动脉环揭开抑制一氧化氮合酶。伊马替尼急性静脉给药可降低肺动脉高压大鼠的高右心室收缩压，对左心室收缩压和心输出量影响不大。我们的结论是酪氨酸激酶抑制剂具有有效的肺血管舒张活性，这可能有助于其对肺动脉高压的长期有益作用。通过激活肌球蛋白轻链磷酸酶（Ca2（+）脱敏）介导的血管平滑肌松弛似乎在伊马替尼诱导的肺血管舒张中发挥作用。
Tyrosine kinase inhibitors are promising for the treatment of severe pulmonary hypertension. Their therapeutic effects are postulated to be due to inhibition of cell growth-related kinases and attenuation of vascular remodeling. Their potential vasodilatory activities have not been explored. Vasorelaxant effects of the tyrosine kinase inhibitors imatinib, sorafenib, and nilotinib were examined in isolated pulmonary arterial rings from normal and pulmonary hypertensive rats. Phosphorylation of myosin light chain phosphatase and myosin light chain was assessed by Western blots. Acute hemodynamic effects of imatinib were tested in the pulmonary hypertensive rats. In normal pulmonary arteries, imatinib reversed serotonin-and U46619-induced contractions in a concentration-dependent and endothelium-independent manner. Sorafenib and nilotinib relaxed U46619-induced contraction. Imatinib inhibited activation of myosin phosphatase induced by U46619 in normal pulmonary arteries. All three tyrosine kinase inhibitors concentration-dependently and completely reversed the spontaneous contraction of hypertensive pulmonary arterial rings unmasked by inhibition of nitric oxide synthase. Acute intravenous administration of imatinib reduced high right ventricular systolic pressure in pulmonary hypertensive rats, with little effect on left ventricular systolic pressure and cardiac output. We conclude that tyrosine kinase inhibitors have potent pulmonary vasodilatory activity, which could contribute to their long-term beneficial effect against pulmonary hypertension. Vascular smooth muscle relaxation mediated via activation of myosin light chain phosphatase (Ca2(+) desensitization) appears to play a role in the imatinib-induced pulmonary vasodilation.