Comparative Efficacy of Angiotensin II Type 1 Receptor Blockers Against Ventilator‐Induced Diaphragm Dysfunction in Rats

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.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Prolonged mechanical ventilation results in ventilator‐induced diaphragm dysfunction (VIDD). This is significant because VIDD is a major risk factor for problems in weaning patients from the ventilator. Currently, no standard treatment exists to prevent VIDD. However, emerging evidence reveals that pharmacological blockade of angiotensin II type 1 receptors (AT1Rs) protects against VIDD. Nonetheless, the specific properties of angiotensin receptor blockers (ARBs) required to protect against VIDD remain unknown.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ What characteristics of ARBs are vital for protection against VIDD?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ ARBs that prevent angiotensin II binding to AT1Rs alone do not protect against VIDD. In contrast, ARBs that block mechanical activation of AT1Rs are protective against VIDD.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ These new findings provide a foundation for future testing of ARBs in clinical trials.

Mechanical ventilation (MV) is used annually in > 13 million patients in the intensive care unit. ¹ Although MV is a life‐saving intervention for many critically ill patients, an unintended consequence of prolonged MV is the rapid development of inspiratory muscle (i.e., diaphragm) weakness. This MV‐induced diaphragmatic weakness is due to both atrophy and contractile dysfunction of the diaphragm, collectively known as ventilator‐induced diaphragm dysfunction (VIDD). ² VIDD is clinically important because diaphragmatic weakness is a major risk factor for problems in “weaning” patients from the ventilator. ³ This failure to wean results in extended time on the ventilator along with increased morbidity and mortality. ⁴ Currently, no standard therapy exists to protect against VIDD.Recent studies into the pathogenesis of VIDD reveal that the renin angiotensin system is a potential therapeutic target to prevent VIDD. Specifically, treatment with the angiotensin II type 1 receptor (AT1R) blocker (ARB) losartan protects against VIDD. ⁵ Although this study reveals that ARBs are protective against VIDD, several classes of ARBs exist and the characteristics of ARBs that provide optimal protection against VIDD remain unknown. In principle, pharmacological blockade of AT1Rs via losartan can avert VIDD by one of three mechanisms. ⁶ , ⁷ , ⁸ First, losartan prevents activation of the classical RAS pathway by blocking angiotensin (AngII) binding to AT1Rs. Second, mechanical stress can activate AT1Rs and losartan blocks mechanical activation of AT1Rs. Indeed, it is feasible that mechanical activation of AT1Rs occurs during MV due to the mechanical stress placed on the receptor due to the passive, repetitive shortening/lengthening cycles of diaphragm fibers during ventilator support. Last, it is possible that losartan protects against VIDD by a combination of blocking both AngII binding and mechanical activation of the AT1R.Prior to clinical trials, additional preclinical studies are required to determine the characteristics of ARBs that are required to protect against VIDD; this forms the rationale for the current study. To delineate the properties of ARBs needed for protection against VIDD, we tested the efficacy of two US Food and Drug Administration (FDA) approved ARBs (i.e., olmesartan and irbesartan) that differ in both molecular structure and effects on the AT1R. Olmesartan blocks both AngII binding and mechanical activation of AT1Rs whereas irbesartan blocks only ligand binding to the receptor. We hypothesized that compared with irbesartan, olmesartan will provide superior protection against VIDD.