Document Detail


The combination of theophylline and endothelin receptor antagonism improves exercise performance of rats under simulated high altitude.
MedLine Citation:
PMID:  22898548     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Decreased physical performance is a well-known consequence of rapid ascent to high altitude. Hypoxic pulmonary vasoconstriction (HPV) potentially limits cardiac output and systemic blood flow, thus preventing successful adaptation to rapid ascent. We hypothesized that pharmacological enhancement of the heart rate with theophylline, combined with reversal of HPV via endothelin blockade, could increase exercise performance at high altitude. Female Sprague-Dawley rats were treated with combinations of 1) theophylline, 2) the endothelin receptor antagonists sitaxsentan/ambrisentan, and/or 3) phosphodiesterase-5 inhibitor sildenafil and exposed to either a simulated high altitude (4,267 m) or 12% oxygen. Exercise capacity, peripheral blood flow, hemodynamics, and pulmonary leak were examined. Combination treatment with theophylline and endothelin blockade, but not with the respective single compounds, significantly prolonged run-to-fatigue time under simulated high altitude. No such efficacy was found when theophylline was combined with sildenafil. Neither theophylline nor sitaxsentan or their combination influenced breathing rates and hemoglobin oxygen saturation. Whereas under hypoxia, theophylline significantly increased muscular blood flow, and sitaxsentan increased tissue oxygenation, the combination improved both parameters but in a reduced manner. Under hypoxia, the combination treatment but not the single compounds significantly enhanced pulmonary arterial pressure compared with controls (13.1 ± 6.3 vs. 11.9 ± 5.2 mmHg), whereas mean arterial pressure remained unaffected. Pulmonary wet-to-dry weight ratios were unaffected by combination treatment. We conclude that concomitant dosing with a cardiac stimulant and endothelin antagonist can partially reverse loss of physical performance capacity under hypobaric hypoxia, independent from improving blood oxygen saturation.
Authors:
Daniel R Radiloff; Yulin Zhao; Alina Boico; Chan Wu; Siqing Shan; Gregory Palmer; Karyn Hamilton; David Irwin; Gabi Hanna; Claude A Piantadosi; Thies Schroeder
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-08-16
Journal Detail:
Title:  Journal of applied physiology (Bethesda, Md. : 1985)     Volume:  113     ISSN:  1522-1601     ISO Abbreviation:  J. Appl. Physiol.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-16     Completed Date:  2013-06-17     Revised Date:  2013-09-26    
Medline Journal Info:
Nlm Unique ID:  8502536     Medline TA:  J Appl Physiol (1985)     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1243-52     Citation Subset:  IM    
Affiliation:
Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
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MeSH Terms
Descriptor/Qualifier:
Altitude
Animals
Anoxia / drug therapy*,  metabolism,  physiopathology*
Arterial Pressure / drug effects,  physiology
Cyclic Nucleotide Phosphodiesterases, Type 5 / metabolism
Drug Synergism
Female
Heart Rate / drug effects,  physiology
Hemodynamics / drug effects,  physiology
Hemoglobins / metabolism
Isoxazoles / pharmacology
Oxygen / metabolism
Phenylpropionates / pharmacology
Physical Conditioning, Animal / physiology*
Piperazines / pharmacology
Pulmonary Artery / drug effects,  physiology
Purines / pharmacology
Pyridazines / pharmacology
Random Allocation
Rats
Rats, Sprague-Dawley
Receptors, Endothelin / antagonists & inhibitors*,  metabolism
Renal Circulation / drug effects,  physiology
Respiration / drug effects
Sulfones / pharmacology
Task Performance and Analysis
Theophylline / pharmacology*
Thiophenes / pharmacology
Vasoconstriction / drug effects,  physiology
Chemical
Reg. No./Substance:
0/Hemoglobins; 0/Isoxazoles; 0/Phenylpropionates; 0/Piperazines; 0/Purines; 0/Pyridazines; 0/Receptors, Endothelin; 0/Sulfones; 0/Thiophenes; 0/sitaxsentan; 177036-94-1/ambrisentan; 3M7OB98Y7H/sildenafil; 58-55-9/Theophylline; 7782-44-7/Oxygen; EC 3.1.4.35/Cyclic Nucleotide Phosphodiesterases, Type 5

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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