Anti-Hypotensive Treatment and Endothelin Blockade Synergistically Antagonize Exercise Fatigue in Rats under Simulated High Altitude

Rapid ascent to high altitude causes illness and fatigue, and there is a demand for effective acute treatments to alleviate such effects. We hypothesized that increased oxygen delivery to the tissue using a combination of a hypertensive agent and an endothelin receptor A antagonist drugs would limit...

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Main Authors:	Radiloff, Daniel, Zhao, Yulin, Boico, Alina, Blueschke, Gert, Palmer, Gregory, Fontanella, Andrew, Dewhirst, Mark, Piantadosi, Claude A., Noveck, Robert, Irwin, David, Hamilton, Karyn, Klitzman, Bruce, Schroeder, Thies
Format:	Online
Language:	English
Published:	Public Library of Science 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4068990/

id	pubmed-4068990
recordtype	oai_dc
spelling	pubmed-40689902014-06-27 Anti-Hypotensive Treatment and Endothelin Blockade Synergistically Antagonize Exercise Fatigue in Rats under Simulated High Altitude Radiloff, Daniel Zhao, Yulin Boico, Alina Blueschke, Gert Palmer, Gregory Fontanella, Andrew Dewhirst, Mark Piantadosi, Claude A. Noveck, Robert Irwin, David Hamilton, Karyn Klitzman, Bruce Schroeder, Thies Research Article Rapid ascent to high altitude causes illness and fatigue, and there is a demand for effective acute treatments to alleviate such effects. We hypothesized that increased oxygen delivery to the tissue using a combination of a hypertensive agent and an endothelin receptor A antagonist drugs would limit exercise-induced fatigue at simulated high altitude. Our data showed that the combination of 0.1 mg/kg ambrisentan with either 20 mg/kg ephedrine or 10 mg/kg methylphenidate significantly improved exercise duration in rats at simulated altitude of 4,267 m, whereas the individual compounds did not. In normoxic, anesthetized rats, ephedrine alone and in combination with ambrisentan increased heart rate, peripheral blood flow, carotid and pulmonary arterial pressures, breathing rate, and vastus lateralis muscle oxygenation, but under inspired hypoxia, only the combination treatment significantly enhanced muscle oxygenation. Our results suggest that sympathomimetic agents combined with endothelin-A receptor blockers offset altitude-induced fatigue in rats by synergistically increasing the delivery rate of oxygen to hypoxic muscle by concomitantly augmenting perfusion pressure and improving capillary conductance in the skeletal muscle. Our findings might therefore serve as a basis to develop an effective treatment to prevent high-altitude illness and fatigue in humans. Public Library of Science 2014-06-24 /pmc/articles/PMC4068990/ /pubmed/24960187 http://dx.doi.org/10.1371/journal.pone.0099309 Text en © 2014 Radiloff et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Radiloff, Daniel Zhao, Yulin Boico, Alina Blueschke, Gert Palmer, Gregory Fontanella, Andrew Dewhirst, Mark Piantadosi, Claude A. Noveck, Robert Irwin, David Hamilton, Karyn Klitzman, Bruce Schroeder, Thies
spellingShingle	Radiloff, Daniel Zhao, Yulin Boico, Alina Blueschke, Gert Palmer, Gregory Fontanella, Andrew Dewhirst, Mark Piantadosi, Claude A. Noveck, Robert Irwin, David Hamilton, Karyn Klitzman, Bruce Schroeder, Thies Anti-Hypotensive Treatment and Endothelin Blockade Synergistically Antagonize Exercise Fatigue in Rats under Simulated High Altitude
author_facet	Radiloff, Daniel Zhao, Yulin Boico, Alina Blueschke, Gert Palmer, Gregory Fontanella, Andrew Dewhirst, Mark Piantadosi, Claude A. Noveck, Robert Irwin, David Hamilton, Karyn Klitzman, Bruce Schroeder, Thies
author_sort	Radiloff, Daniel
title	Anti-Hypotensive Treatment and Endothelin Blockade Synergistically Antagonize Exercise Fatigue in Rats under Simulated High Altitude
title_short	Anti-Hypotensive Treatment and Endothelin Blockade Synergistically Antagonize Exercise Fatigue in Rats under Simulated High Altitude
title_full	Anti-Hypotensive Treatment and Endothelin Blockade Synergistically Antagonize Exercise Fatigue in Rats under Simulated High Altitude
title_fullStr	Anti-Hypotensive Treatment and Endothelin Blockade Synergistically Antagonize Exercise Fatigue in Rats under Simulated High Altitude
title_full_unstemmed	Anti-Hypotensive Treatment and Endothelin Blockade Synergistically Antagonize Exercise Fatigue in Rats under Simulated High Altitude
title_sort	anti-hypotensive treatment and endothelin blockade synergistically antagonize exercise fatigue in rats under simulated high altitude
description	Rapid ascent to high altitude causes illness and fatigue, and there is a demand for effective acute treatments to alleviate such effects. We hypothesized that increased oxygen delivery to the tissue using a combination of a hypertensive agent and an endothelin receptor A antagonist drugs would limit exercise-induced fatigue at simulated high altitude. Our data showed that the combination of 0.1 mg/kg ambrisentan with either 20 mg/kg ephedrine or 10 mg/kg methylphenidate significantly improved exercise duration in rats at simulated altitude of 4,267 m, whereas the individual compounds did not. In normoxic, anesthetized rats, ephedrine alone and in combination with ambrisentan increased heart rate, peripheral blood flow, carotid and pulmonary arterial pressures, breathing rate, and vastus lateralis muscle oxygenation, but under inspired hypoxia, only the combination treatment significantly enhanced muscle oxygenation. Our results suggest that sympathomimetic agents combined with endothelin-A receptor blockers offset altitude-induced fatigue in rats by synergistically increasing the delivery rate of oxygen to hypoxic muscle by concomitantly augmenting perfusion pressure and improving capillary conductance in the skeletal muscle. Our findings might therefore serve as a basis to develop an effective treatment to prevent high-altitude illness and fatigue in humans.
publisher	Public Library of Science
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4068990/
_version_	1612105455935422464

Anti-Hypotensive Treatment and Endothelin Blockade Synergistically Antagonize Exercise Fatigue in Rats under Simulated High Altitude

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