Departments of Pharmacology and Medicine (Pulmonary Diseases, Critical Care and Environmental Medicine Tulane University School of Medicine, New Orleans, Louisiana.
Am J Physiol Heart Circ Physiol. 2013 Nov 1;305(9):H1288-96. doi: 10.1152/ajpheart.00329.2013. Epub 2013 Aug 30.
Cardiovascular responses to the tyrosine kinase inhibitor imatinib were investigated in the rat. Intravenous injections of 0.3-30 mg/kg imatinib produced small decreases in pulmonary arterial pressure, larger dose-dependent decreases in systemic arterial pressure, and no change or small increases in cardiac output, suggesting that the systemic vasodilator response is more pronounced under baseline conditions. When pulmonary arterial pressure was increased with U-46619 or N(ω)-nitro-L-arginine methyl ester (L-NAME), intravenous injections of imatinib produced larger dose-dependent decreases in pulmonary arterial pressure. Imatinib attenuated the acute hypoxic pulmonary vasoconstrictor response. Vasodilator responses to imatinib were not inhibited by meclofenamate, glybenclamide, or rolipram, suggesting that cyclooxygenase, ATP-sensitive K(+) (KATP) channels, and cAMP were not involved in mediating the response. In a 21-day prevention study, imatinib treatment (50 mg/kg ip) attenuated the increase in pulmonary arterial pressure, right ventricular hypertrophy, and small vessel remodeling induced by monocrotaline. Imatinib reduced PDGF receptor phosphorylation and PDGF-stimulated thymidine incorporation in rat pulmonary artery smooth muscle cells. These data suggest that the beneficial effect of imatinib in pulmonary hypertension may involve inhibition of PDGF tyrosine kinase receptor-mediated effects on smooth muscle cell proliferation and on vasoconstrictor tone. These results indicate that imatinib has nonselective vasodilator activity in the pulmonary and systemic vascular beds similar to the Rho kinase inhibitor fasudil and the calcium entry antagonist isradipine. The present results are consistent with the hypothesis that imatinib may inhibit a constitutively active tyrosine kinase vasoconstrictor pathway in the pulmonary and systemic vascular beds in the rat.
研究了酪氨酸激酶抑制剂伊马替尼对大鼠心血管的反应。静脉注射 0.3-30mg/kg 的伊马替尼可使肺动脉压略有下降，较大剂量的伊马替尼则使体动脉压呈剂量依赖性下降，心输出量无变化或略有增加，提示在基础状态下，全身血管扩张反应更为明显。当用 U-46619 或 N(ω)-硝基-L-精氨酸甲酯（L-NAME）升高肺动脉压时，静脉注射伊马替尼可使肺动脉压进一步显著下降。伊马替尼可减弱急性低氧性肺血管收缩反应。伊马替尼的血管扩张反应不受美洛昔康、格列本脲或罗利普兰的抑制，提示环氧化酶、ATP 敏感性 K(+)（KATP）通道和 cAMP 不参与介导该反应。在 21 天预防研究中，伊马替尼治疗（50mg/kg ip）可减轻野百合碱诱导的肺动脉压升高、右心室肥厚和小血管重构。伊马替尼降低 PDGF 受体磷酸化和 PDGF 刺激的大鼠肺动脉平滑肌细胞胸苷掺入。这些数据表明，伊马替尼在肺动脉高压中的有益作用可能涉及抑制 PDGF 酪氨酸激酶受体介导的平滑肌细胞增殖和血管收缩作用。这些结果表明，伊马替尼在肺和体循环血管床中具有非选择性血管扩张活性，类似于 Rho 激酶抑制剂法舒地尔和钙通道拮抗剂异搏定。目前的结果与假设一致，即伊马替尼可能抑制大鼠肺和体循环血管床中一种固有活性的酪氨酸激酶血管收缩途径。
