Comparative Efficacy of Angiotensin II Type 1 Receptor Blockers Against Ventilator-Induced Diaphragm Dysfunction in Rats.
Comparative Efficacy of Angiotensin II Type 1 Receptor Blockers Against Ventilator-Induced Diaphragm Dysfunction in Rats.
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血管紧张素II 1型受体阻滞剂对大鼠呼吸机诱导的膈肌功能障碍的疗效比较。
DOI：
10.1111/cts.12916
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Powers SK
中科院分区：
文献类型：
--
作者：
Hall SE;Ahn B;Smuder AJ;Morton AB;Hinkley JM;Wiggs MP;Sollanek KJ;Hyatt H;Powers SK
机械通气（MV）是许多危重患者的救命干预措施。不幸的是，MV延长会导致由于呼吸肌萎缩和收缩功能障碍（称为呼吸机诱导的膈肌功能障碍（VIDD））导致的吸气肌无力的快速发展。尽管VIDD是导致患者脱离MV的主要风险因素，但并不存在预防VIDD的标准治疗。然而，新出现的证据表明，血管紧张素II 1型受体（AT 1 R）的药理学阻断可预防VIDD。尽管如此，AT 1 R阻滞剂（ARB）保护VIDD所需的基本特征仍不清楚。为了确定ARB对预防VIDD至关重要的特征，我们比较了两种临床相关ARB（厄贝沙坦和奥美沙坦）的疗效;这些ARB在分子结构和对AT 1 R的影响方面不同。具体而言，奥美沙坦阻断血管紧张素II（AngII）结合和AT 1 R的机械活化，而厄贝沙坦仅阻止AngII与AT 1 R结合。使用一个成熟的MV延长的临床前模型，我们检验了与厄贝沙坦相比，奥美沙坦对VIDD的保护作用更强的假设。我们的研究结果表明，厄贝沙坦不能预防VIDD，而奥美沙坦可以预防MV诱导的血管萎缩和收缩功能障碍。这些结果支持奥美沙坦在预防VIDD方面上级厄贝沙坦的假设，并且与阻断AT 1 R的机械激活是ARB预防VIDD所需的特性的概念一致。这些重要的发现为未来的临床试验提供了基础，以评估ARB作为预防VIDD的治疗方法。
Mechanical ventilation (MV) is a life‐saving intervention for many critically ill patients. Unfortunately, prolonged MV results in the rapid development of inspiratory muscle weakness due to diaphragmatic atrophy and contractile dysfunction (termed ventilator‐induced diaphragm dysfunction (VIDD)). Although VIDD is a major risk factor for problems in weaning patients from MV, a standard therapy to prevent VIDD does not exist. However, emerging evidence suggests that pharmacological blockade of angiotensin II type 1 receptors (AT1Rs) protects against VIDD. Nonetheless, the essential characteristics of AT1R blockers (ARBs) required to protect against VIDD remain unclear. To determine the traits of ARBs that are vital for protection against VIDD, we compared the efficacy of two clinically relevant ARBs, irbesartan and olmesartan; these ARBs differ in molecular structure and effects on AT1Rs. Specifically, olmesartan blocks both angiotensin II (AngII) binding and mechanical activation of AT1Rs, whereas irbesartan prevents only AngII binding to AT1Rs. Using a well‐established preclinical model of prolonged MV, we tested the hypothesis that compared with irbesartan, olmesartan provides greater protection against VIDD. Our results reveal that irbesartan does not protect against VIDD whereas olmesartan defends against both MV‐induced diaphragmatic atrophy and contractile dysfunction. These findings support the hypothesis that olmesartan is superior to irbesartan in protecting against VIDD and are consistent with the concept that blockade of mechanical activation of AT1Rs is a required property of ARBs to shield against VIDD. These important findings provide a foundation for future clinical trials to evaluate ARBs as a therapy to protect against VIDD.
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影响因子：
3.3
作者：
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