AT1 receptor blocker losartan protects against mechanical ventilation-induced diaphragmatic dysfunction
AT1 receptor blocker losartan protects against mechanical ventilation-induced diaphragmatic dysfunction
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DOI：
10.1152/japplphysiol.00237.2015
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发表时间：
2015-11-15
影响因子：
3.3
通讯作者：
Powers, Scott K.
中科院分区：
文献类型：
--
作者：
Kwon, Oh Sung;Smuder, Ashley J.;Powers, Scott K.
机械通气是呼吸衰竭患者的救命手段。不幸的是，长时间的呼吸机支持会导致膈肌萎缩和收缩功能障碍，导致膈肌无力，预计这将导致患者脱离呼吸机的问题。虽然已经确定呼吸机诱导的氧化应激对于呼吸机诱导的膈肌无力的发展是必需的，但触发氧化剂产生的信号通路仍然未知。然而，最近的证据表明，血浆血管紧张素II （ANG II）水平升高导致肢体骨骼肌氧化应激和萎缩。使用一个完善的机械通气动物模型，我们验证了一个假设，即呼吸机诱导的膈膜氧化应激和膈肌无力都需要增加循环中ANG II水平。通过给予血管紧张素转换酶抑制剂（依那普利）以防止呼吸机诱导的血浆ANG II水平升高来确定因果关系，并提供ANG II 1型受体拮抗剂（氯沙坦）以防止ANG II 1型受体的激活。依那普利阻止血浆ANG II水平升高，但对呼吸机诱导的膈肌氧化应激或膈肌无力没有保护作用。相反，氯沙坦可以减轻呼吸机诱导的氧化应激和膈肌无力。这些发现表明，循环的ANG II对呼吸机诱导的膈肌无力的发展并不是必需的，但ANG II 1型受体的激活似乎是呼吸机诱导的膈肌无力的必要条件。重要的是，这些实验提供了第一个证据，证明食品和药物管理局批准的药物氯沙坦可能具有临床益处，可以保护人类免受呼吸机引起的膈肌无力。
Mechanical ventilation is a life-saving intervention for patients in respiratory failure. Unfortunately, prolonged ventilator support results in diaphragmatic atrophy and contractile dysfunction leading to diaphragm weakness, which is predicted to contribute to problems in weaning patients from the ventilator. While it is established that ventilator-induced oxidative stress is required for the development of ventilator-induced diaphragm weakness, the signaling pathway(s) that trigger oxidant production remain unknown. However, recent evidence reveals that increased plasma levels of angiotensin II (ANG II) result in oxidative stress and atrophy in limb skeletal muscles. Using a well-established animal model of mechanical ventilation, we tested the hypothesis that increased circulating levels of ANG II are required for both ventilator-induced diaphragmatic oxidative stress and diaphragm weakness. Cause and effect was determined by administering an angiotensin-converting enzyme inhibitor (enalapril) to prevent ventilator-induced increases in plasma ANG II levels, and the ANG II type 1 receptor antagonist (losartan) was provided to prevent the activation of ANG II type 1 receptors. Enalapril prevented the increase in plasma ANG II levels but did not protect against ventilator-induced diaphragmatic oxidative stress or diaphragm weakness. In contrast, losartan attenuated both ventilator-induced oxidative stress and diaphragm weakness. These findings indicate that circulating ANG II is not essential for the development of ventilator-induced diaphragm weakness but that activation of ANG II type 1 receptors appears to be a requirement for ventilator-induced diaphragm weakness. Importantly, these experiments provide the first evidence that the Food and Drug Administration-approved drug losartan may have clinical benefits to protect against ventilator-induced diaphragm weakness in humans.