Stretch Activation of Angiotensin II Type 1 Receptor Contributes to Ventilatorinduced Diaphragm Dysfunction
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abstract
Mechanical ventilation (MV) is a lifesaving intervention for patients in respiratory failure. Unfortunately, prolonged MV results in diaphragmatic atrophy and contractile dysfunction (collectively termed ventilatorinduced diaphragm dysfunction, VIDD). The development of VIDD is important because diaphragm weakness can contribute to problems in weaning patients from MV. Currently, no standard treatment exists to prevent VIDD and understanding the causation of VIDD is vital for the development of a therapeutic intervention. Recent evidence reveals that increased plasma levels of Angiotensin II (Ang II) promotes oxidative stress and fiber atrophy in limb muscles. Our preliminary experiments suggest that Ang II type 1 receptor (AT1R) activation contributes to VIDD but MVinduced AT1R activation in the diaphragm is independent of circulating Ang II levels. Therefore, using animal rat model of MV, we tested the hypothesis that MVinduced stretch activation of AT1R in the diaphragm is required for the development VIDD. Two structurally different AT1R antagonists were administered during 12 hours of MV. Olmesartan has an ideal chemical structure to inhibit stretchinduced AT1R activation whereas irbesartan does not prevent stretchinduced AT1R activation. Both drugs are effective at blocking Ang II binding to AT1R. Treatment of animals with olmesartan protected against VIDD whereas irbesartan did not protect against VIDD. These results suggest that stretch activation of AT1R is essential for the development of VIDD. Importantly, these experiments provide evidence that the FDA approved drug olmesartan may have clinical benefits in the protection against VIDD in humans.
