ANGIOTENSIN II TYPE 1 RECEPTOR CONTRIBUTES TO VENTILATOR-INDUCED DIAPHRAGM DYSFUNCTION

S. E. Hall1, A. J. Smuder2, M. P. Wiggs2, A. B. Morton2, K. J. Sollanek2, S. K. Powers2 1 Boise State University, Boise, ID & 2 University of Florida, Gainesville, FL Mechanical ventilation (MV) is a life-saving intervention for patients in respiratory failure. Unfortunately, prolonged MV results in diaphragmatic atrophy and contractile dysfunction (collectively termed ventilator-induced 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 skeletal muscles. Our preliminary experiments suggest that Ang II type 1 receptor (AT1R) activation contributes to VIDD, however, MV-induced AT1R activation in the diaphragm is independent of circulating Ang II levels. Indeed, the AT1R activation could be the result of mechanical stretch of the receptor during the passive length change of the diaphragm during MV. PURPOSE: Test the hypothesis that MV-induced stretch activation of AT1R in the diaphragm is required for the development VIDD. METHODS: Two structurally different AT1R antagonists were administered during 12 hours of MV. Olmesartan has an ideal chemical structure to inhibit stretch-induced AT1R activation whereas irbesartan does not prevent stretch-induced AT1R activation. Both drugs are effective at blocking Ang II binding to AT1R. Following MV, animals were sacrificed and measures of VIDD were performed. RESULTS: Treatment of animals with Olmesartan protected against VIDD whereas irbesartan did not protect against VIDD, as determined by contractile force and cross sectional area. Diaphragm contractile force at 160 Hz (in addition to other frequencies) was significantly improved in the MV-Olmesartan group (22.8 N/cm2) compared to the MV group (21.2 N/cm2), p\u3c.05. In addition, the decrease in cross sectional area seen with MV was attenuated by only olmesartan across all fiber types; type I (905.3 μm2 vs. 1205.4 μm2), type IIa (991.0 μm2 vs. 1351.0 μm2), and type IIb/x (2336.9 μm2 vs. 2891.0 μm2), p\u3c.05. CONCLUSION: 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