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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)). A...

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Autores principales: Hall, Stephanie E., Ahn, Bumsoo, Smuder, Ashley J., Morton, Aaron B., Hinkley, J. Matthew, Wiggs, Michael P., Sollanek, Kurt J., Hyatt, Hayden, Powers, Scott K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993256/
https://www.ncbi.nlm.nih.gov/pubmed/33222389
http://dx.doi.org/10.1111/cts.12916
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author Hall, Stephanie E.
Ahn, Bumsoo
Smuder, Ashley J.
Morton, Aaron B.
Hinkley, J. Matthew
Wiggs, Michael P.
Sollanek, Kurt J.
Hyatt, Hayden
Powers, Scott K.
author_facet Hall, Stephanie E.
Ahn, Bumsoo
Smuder, Ashley J.
Morton, Aaron B.
Hinkley, J. Matthew
Wiggs, Michael P.
Sollanek, Kurt J.
Hyatt, Hayden
Powers, Scott K.
author_sort Hall, Stephanie E.
collection PubMed
description 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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spelling pubmed-79932562021-03-29 Comparative Efficacy of Angiotensin II Type 1 Receptor Blockers Against Ventilator‐Induced Diaphragm Dysfunction in Rats Hall, Stephanie E. Ahn, Bumsoo Smuder, Ashley J. Morton, Aaron B. Hinkley, J. Matthew Wiggs, Michael P. Sollanek, Kurt J. Hyatt, Hayden Powers, Scott K. Clin Transl Sci Research 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. John Wiley and Sons Inc. 2020-11-22 2021-03 /pmc/articles/PMC7993256/ /pubmed/33222389 http://dx.doi.org/10.1111/cts.12916 Text en © 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Research
Hall, Stephanie E.
Ahn, Bumsoo
Smuder, Ashley J.
Morton, Aaron B.
Hinkley, J. Matthew
Wiggs, Michael P.
Sollanek, Kurt J.
Hyatt, Hayden
Powers, Scott K.
Comparative Efficacy of Angiotensin II Type 1 Receptor Blockers Against Ventilator‐Induced Diaphragm Dysfunction in Rats
title Comparative Efficacy of Angiotensin II Type 1 Receptor Blockers Against Ventilator‐Induced Diaphragm Dysfunction in Rats
title_full Comparative Efficacy of Angiotensin II Type 1 Receptor Blockers Against Ventilator‐Induced Diaphragm Dysfunction in Rats
title_fullStr Comparative Efficacy of Angiotensin II Type 1 Receptor Blockers Against Ventilator‐Induced Diaphragm Dysfunction in Rats
title_full_unstemmed Comparative Efficacy of Angiotensin II Type 1 Receptor Blockers Against Ventilator‐Induced Diaphragm Dysfunction in Rats
title_short Comparative Efficacy of Angiotensin II Type 1 Receptor Blockers Against Ventilator‐Induced Diaphragm Dysfunction in Rats
title_sort comparative efficacy of angiotensin ii type 1 receptor blockers against ventilator‐induced diaphragm dysfunction in rats
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993256/
https://www.ncbi.nlm.nih.gov/pubmed/33222389
http://dx.doi.org/10.1111/cts.12916
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