Department of Anatomy and Physiology, Kansas State University, Manhattan, Kansas, USA.
Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
Clin Transl Sci. 2021 Mar;14(2):481-486. doi: 10.1111/cts.12916. Epub 2020 Nov 22.
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.
机械通气（MV）是许多危重病患者的救命干预措施。不幸的是，由于膈肌萎缩和收缩功能障碍，长时间的 MV 导致吸气肌无力迅速发展（称为呼吸机诱导的膈肌功能障碍（VIDD））。尽管 VIDD 是患者从 MV 脱机困难的主要危险因素，但不存在预防 VIDD 的标准治疗方法。然而，新出现的证据表明，血管紧张素 II 型 1 受体（AT1R）的药理学阻断可预防 VIDD。尽管如此，防止 VIDD 所需的 AT1R 阻滞剂（ARB）的基本特征仍不清楚。为了确定 ARB 预防 VIDD 所必需的特征，我们比较了两种临床相关的 ARB，厄贝沙坦和奥美沙坦的疗效；这些 ARB 在分子结构和对 AT1R 的作用上有所不同。具体而言，奥美沙坦阻断血管紧张素 II（AngII）与 AT1R 的结合和机械激活，而厄贝沙坦仅防止 AngII 与 AT1R 的结合。使用经过充分验证的长期 MV 临床前模型，我们检验了这样一个假设，即与厄贝沙坦相比，奥美沙坦对 VIDD 提供更大的保护作用。我们的结果表明，厄贝沙坦不能预防 VIDD，而奥美沙坦可预防 MV 诱导的膈肌萎缩和收缩功能障碍。这些发现支持奥美沙坦在预防 VIDD 方面优于厄贝沙坦的假设，并且与机械激活 AT1R 的阻断是 ARB 预防 VIDD 所必需的特性的概念一致。这些重要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。
