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    Anti-hypotensive treatment and endothelin blockade synergistically antagonize exercise fatigue in rats under simulated high altitude.

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    Date
    2014
    Authors
    Blueschke, G
    Boico, A
    Dewhirst, Mark Wesley
    Fontanella, Andrew N
    Hamilton, K
    Irwin, D
    Klitzman, Bruce
    Noveck, Robert
    Palmer, Gregory M
    Piantadosi, Claude Anthony
    Radiloff, D
    Schroeder, T
    Zhao, Y
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    Abstract
    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.
    Type
    Journal article
    Subject
    Acclimatization
    Altitude
    Altitude Sickness
    Animals
    Cell Hypoxia
    Disease Models, Animal
    Dose-Response Relationship, Drug
    Drug Synergism
    Drug Therapy, Combination
    Endothelin A Receptor Antagonists
    Ephedrine
    Fatigue
    Injections, Intraperitoneal
    Methylphenidate
    Phenylpropionates
    Pyridazines
    Rats
    Sympathomimetics
    Permalink
    https://hdl.handle.net/10161/10340
    Published Version (Please cite this version)
    10.1371/journal.pone.0099309
    Publication Info
    Blueschke, G; Boico, A; Dewhirst, Mark Wesley; Fontanella, Andrew N; Hamilton, K; Irwin, D; ... Zhao, Y (2014). Anti-hypotensive treatment and endothelin blockade synergistically antagonize exercise fatigue in rats under simulated high altitude. PLoS One, 9(6). pp. e99309. 10.1371/journal.pone.0099309. Retrieved from https://hdl.handle.net/10161/10340.
    This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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    Scholars@Duke

    Dewhirst

    Mark Wesley Dewhirst

    Gustavo S. Montana Professor Emeritus of Radiation Oncology
    Mark W. Dewhirst, DVM, PhD is the Gustavo S. Montana Professor of Radiation Oncology and Vice Director for Basic Science in the Duke Cancer Institute. Dr. Dewhirst has research interests in tumor hypoxia, angiogenesis, hyperthermia and drug transport. He has spent 30 years studying causes of tumor hypoxia and the use of hyperthermia to treat cancer. In collaboration with Professor David Needham in the Pratt School of Engineering, he has developed a novel thermally sensitive drug carrying liposom
    Klitzman

    Bruce Klitzman

    Associate Professor of Surgery
    Our overriding interests are in the fields of tissue engineering, wound healing, biosensors, and long term improvement of medical device implantation. My basic research interests are in the area of physiological mechanisms of optimizing substrate transport to tissue. This broad topic covers studies on a whole animal, whole organ, hemorheological, microvascular, cellular, ultrastructural, and molecular level. The current projects include: 1) control of blood flow and flow distribu

    Robert Joseph Noveck

    Associate Professor of Medicine
    Palmer

    Gregory M. Palmer

    Associate Professor of Radiation Oncology
    Greg Palmer obtained his B.S. in Biomedical Engineering from Marquette University in 2000, after which he obtained his Ph.D. in BME from the University of Wisconsin, Madison. He is currently an Associate Professor in the Department of Radiation Oncology, Cancer Biology Division at Duke University Medical Center. His primary research focus has been identifying and exploiting the changes in absorption, scattering, and fluorescence properties of tissue associated with cancer progression and therape
    Piantadosi

    Claude Anthony Piantadosi

    Professor of Medicine
    Dr. Piantadosi's laboratory has special expertise in the pathogenic mechanisms of acute organ failure, particularly acute lung injury (ALI), with an emphasis on the molecular regulatory roles of the physiological gases— oxygen, carbon monoxide, and nitric oxide— as they relate to the damage responses to acute inflammation. The basic science focuses on oxidative processes and redox-regulation, especially the molecular mechanisms by which reactive oxygen and nitrogen species trans
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