Anti-ischemic effects of fasudil, a specific Rho-kinase inhibitor, in patients with stable effort angina
Anti-ischemic effects of fasudil, a specific Rho-kinase inhibitor, in patients with stable effort angina
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DOI：
10.1097/fjc.0b013e31802ef532
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发表时间：
2007-03-01
影响因子：
3
通讯作者：
Shimokawa, Hiroaki
中科院分区：
文献类型：
--
作者：
Fukumoto, Yoshihiro;Mohri, Masahiro;Shimokawa, Hiroaki
心外膜冠状动脉狭窄导致心肌缺血;然而，冠状动脉微血管在劳力型心绞痛发病机制中的作用知之甚少。我们以前已经证明，Rho激酶途径在血管痉挛性心绞痛和微血管性心绞痛患者的冠状动脉过度收缩中有重要作用。在本研究中，我们验证了我们的假设，即Rho激酶参与了劳力型心绞痛患者的冠状动脉微血管收缩。冠状动脉内注射法舒地尔（300 μ g/min，15 min），一种特异性Rho激酶抑制剂，使冠状静脉窦血氧饱和度从37 +/- 3%显著增加到41 +/- 3%（P < 0.05），但在6个年龄匹配的对照组中没有增加（从42 +/- 3%增加到43 3%，P = NS）。此外，法舒地尔治疗显著改善了劳力型心绞痛患者起搏引起的心肌缺血（症状程度：1.5 +/- 0.6至0.6 +/- 0.4，P < 0.01;缺血性ST段压低，1.8 +/- 0.3至1.0 +/- 0.2 mm，P < 0.01;乳酸产生百分比，50 +/- 17%至0.4 +/-7%，P < 0.01），无显著血流动力学变化。这些结果提供了第一个证据表明Rho激酶实质上参与了与劳力型心绞痛患者心肌缺血相关的冠状动脉微血管功能障碍，表明Rho激酶可能是缺血性心脏病的新治疗靶点。
Epicardial coronary stenosis causes myocardial ischemia; however, the role of coronary microvessels is poorly understood in the pathogenesis of effort angina. We have previously demonstrated that Rho-kinase pathway is substantially involved in coronary arterial hyperconstriction in patients with vasospastic angina and those with microvascular angina. In the present study, we tested our hypothesis that Rho-kinase is involved in coronary microvascular constriction in patients with effort angina. Intracoronary administration of fasudil (300 mu g/min for 15 min), a specific Rho-kinase inhibitor, significantly increased oxygen saturation in coronary sinus vein from 37 +/- 3% to 41 +/- 3% (P < 0.05) but not in six age-matched controls (from 42 +/- 3% to 43 3%, P = NS). Furthermore, the fasudil treatment significantly ameliorated pacing-induced myocardial ischemia in patients with effort angina (magnitudes of symptom: 1.5 +/- 0.6 to 0.6 +/- 0.4, P < 0.01; ischemic ST-segment depression, 1.8 +/- 0.3 to 1.0 +/- 0.2 mm, P < 0.01; percent lactate production, 50 +/- 17% to 0.4 +/- 7%, P < 0.01) without significant hemodynamic changes. These results provide the first evidence that Rho-kinase is substantially involved in coronary microvascular dysfunction associated with myocardial ischemia in patients with effort angina, suggesting that Rho-kinase can be a novel therapeutic target in ischemic heart disease.