title: Anti-hypotensive treatment and endothelin blockade synergistically antagonize exercise fatigue in rats under simulated high altitude.
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.
authors: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors: Daniel
authors: D
authors: Radiloff
authors: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors: Yulin
authors: Y
authors: Zhao
authors: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors: Alina
authors: A
authors: Boico
authors: Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States of America.
authors: Gert
authors: G
authors: Blueschke
authors: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors: Gregory
authors: G
authors: Palmer
authors: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors: Andrew
authors: A
authors: Fontanella
authors: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors: Mark
authors: M
authors: Dewhirst
authors: Department of Medicine-Pulmonary, Duke University Medical Center, Durham, North Carolina, United States of America.
authors: Claude A
authors: CA
authors: Piantadosi
authors: Department of Medicine-Clinical Pharmacology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors: Robert
authors: R
authors: Noveck
authors: Department of Cardiology, University of Colorado Denver, Aurora, Colorado, United States of America.
authors: David
authors: D
authors: Irwin
authors: Department of Health and Exercise Science, Colorado State University, Fort Collins, Colorado, United States of America.
authors: Karyn
authors: K
authors: Hamilton
authors: Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States of America.
authors: Bruce
authors: B
authors: Klitzman
authors: Department of Physical Chemistry, University of Mainz, Mainz, Germany.
authors: Thies
authors: T
authors: Schroeder
mesh_terms: D000064:Acclimatization; D000531:Altitude; D000532:Altitude Sickness / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D065130:Endothelin A Receptor Antagonists / Q000008:administration & dosage*; D004809:Ephedrine / Q000008:administration & dosage*; D005221:Fatigue / Q000188:drug therapy* / Q000503:physiopathology; D007274:Injections, Intraperitoneal; D008774:Methylphenidate / Q000008:administration & dosage*; D010666:Phenylpropionates / Q000008:administration & dosage*; D011724:Pyridazines / Q000008:administration & dosage*; D051381:Rats; D013566:Sympathomimetics / Q000008:administration & dosage*
chemical_list: D065130:Endothelin A Receptor Antagonists; D010666:Phenylpropionates; D011724:Pyridazines; D013566:Sympathomimetics; D008774:Methylphenidate; D004809:Ephedrine; C467894:ambrisentan