Imatinib attenuates monocrotaline pulmonary hypertension and has potent vasodilator activity in pulmonary and systemic vascular beds in the rat
Imatinib attenuates monocrotaline pulmonary hypertension and has potent vasodilator activity in pulmonary and systemic vascular beds in the rat
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DOI：
10.1152/ajpheart.00329.2013
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发表时间：
2013-11-01
影响因子：
4.8
通讯作者：
Kadowitz, Philip J.
中科院分区：
文献类型：
--
作者：
Pankey, Edward A.;Thammasiboon, Supat;Kadowitz, Philip J.
研究了酪氨酸激酶抑制剂伊马替尼对大鼠的心血管反应。静脉注射伊马替尼0.3~30 mg/kg时，肺动脉压下降幅度较小，体动脉压下降幅度较大，心输出量无明显变化或略有增加，提示基础状态下全身血管扩张反应更为明显。当用U-46619或N-奥米伽-硝基-L-精氨酸甲酯(L-NAME)升高肺动脉压时，静脉注射伊马替尼引起的肺动脉压下降呈剂量依赖性。伊马替尼可减轻急性缺氧性肺血管收缩反应。甲氯芬酸酯、格列本脲或罗利普兰不抑制伊马替尼的血管扩张反应，提示环氧合酶、ATP敏感性K+(KATP)通道和cAMP不参与介导该反应。在一项为期21天的预防研究中，伊马替尼治疗(50 mg/kg ip)减轻了野百合碱引起的肺动脉压升高、右室肥厚和小血管重构。伊马替尼降低大鼠肺动脉平滑肌细胞PDGF受体的磷酸化和PDGF刺激的胸腺嘧啶核苷掺入。这些数据提示，伊马替尼治疗肺动脉高压的有益作用可能与抑制PDGF酪氨酸激酶受体介导的血管收缩张力和平滑肌细胞增殖有关。这些结果表明，伊马替尼在肺和全身血管床上具有与Rho激酶抑制剂法舒地尔和钙通道拮抗剂伊拉地平相似的非选择性血管扩张活性。目前的结果与伊马替尼可能抑制大鼠肺和全身血管床上具有结构性活性的酪氨酸激酶血管收缩通路的假说一致。
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-omega-nitro-L-arginine methyl ester (L-NAME), intravenous injections of imatinib produced larger dosedependent 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, ATPsensitive 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.