Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
J Heart Lung Transplant. 2011 Mar;30(3):332-40. doi: 10.1016/j.healun.2010.09.011. Epub 2010 Nov 13.
The possible mechanisms of simvastatin attenuating pulmonary hypertension (PH) have been widely investigated in pulmonary vascular and hemodynamic systems, but few studies have examined the difference in respiratory response mediated by pulmonary C fibers (PCF) in animal models of PH. We hypothesized that PCF sensitivity would differ from normal in monocrotaline-induced pulmonary hypertension (MCT-PH) rats and the effects of simvastatin treatment would involve not only the pulmonary circulatory system, but also PCF sensitivity.
The PCF sensitivity was investigated by measuring the apneic durations evoked by 3 chemical stimulants: capsaicin; α,β-methylene-adenosine triphosphate; and phenylbiguanide. The effects of simvastatin on PCF sensitivity were evaluated in the MCT-PH rat model.
The sensitivity of PCF was increased significantly after monocrotaline (MCT) application for 21 days. Bilateral vagatomy and high-dose perivagal capsaicin (250 μg/ml) treatment both blocked the PCF hypersensitivity induced by MCT. Three days of simvastatin (5 mg/kg) treatment significantly reduced the hypersensitive status of PCF. In MCT-PH rats, reactive oxygen species (ROS) production was significantly elevated in both blood and bronchoalveolar lavage, but both showed a significantly decrease after simvastatin treatment. These potential benefits of simvastatin were all abolished by co-application of tin protoporphyrin-IX (SnPP), a specific heme oxygenase-1 (HO-1) inhibitor.
Simvastatin treatment in MCT-PH rats not only attenuated pulmonary hypertension, but also desensitized PCF hypersensitivity and decreased the production of ROS. These cholesterol-independent effects were mainly through the HO-1 pathway and may all contribute to the therapeutic effects of PH treatment.
辛伐他汀减轻肺动脉高压（PH）的可能机制已在肺血管和血液动力学系统中得到广泛研究，但很少有研究在 PH 动物模型中检测到肺 C 纤维（PCF）介导的呼吸反应差异。我们假设，在野百合碱诱导的肺动脉高压（MCT-PH）大鼠中，PCF 的敏感性与正常情况不同，辛伐他汀的治疗效果不仅涉及肺循环系统，还涉及 PCF 的敏感性。
通过测量 3 种化学刺激物（辣椒素、α，β-亚甲基-三磷酸腺苷和苯并胍）引起的呼吸暂停持续时间来研究 PCF 的敏感性。在 MCT-PH 大鼠模型中评估辛伐他汀对 PCF 敏感性的影响。
野百合碱（MCT）应用 21 天后，PCF 的敏感性显著增加。双侧迷走神经切断术和高剂量周围神经辣椒素（250μg/ml）处理均阻断了 MCT 诱导的 PCF 高敏性。3 天的辛伐他汀（5mg/kg）治疗显著降低了 PCF 的高敏状态。在 MCT-PH 大鼠中，血液和支气管肺泡灌洗液中的活性氧（ROS）生成均显著升高，但辛伐他汀治疗后均显著降低。辛伐他汀的这些潜在益处均被血红素加氧酶-1（HO-1）抑制剂锡原卟啉-IX（SnPP）的共同应用所消除。
在 MCT-PH 大鼠中，辛伐他汀治疗不仅减轻了肺动脉高压，还使 PCF 高敏性脱敏，降低了 ROS 的产生。这些与胆固醇无关的作用主要通过 HO-1 途径，可能都有助于 PH 治疗的疗效。
