The combination of theophylline and endothelin receptor antagonism improves exercise performance of rats under simulated high altitude.

Abstract

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
• Journal: Journal of applied physiology (Bethesda, Md. : 1985) (J Appl Physiol (1985)) Vol. 113 Issue 8 Pg. 1243-52 (Oct 15 2012) ISSN: 1522-1601 [Electronic] United States
• PMID: 22898548 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Endothelin Receptor Antagonists
• Hemoglobins
• Isoxazoles
• Phenylpropionates
• Piperazines
• Purines
• Pyridazines
• Receptors, Endothelin
• Sulfones
• Thiophenes
• Sildenafil Citrate
• Theophylline
• Cyclic Nucleotide Phosphodiesterases, Type 5
• ambrisentan
• sitaxsentan
• Oxygen

Topics

• Altitude
• Animals
• Arterial Pressure (drug effects, physiology)
• Cyclic Nucleotide Phosphodiesterases, Type 5 (metabolism)
• Drug Synergism
• Endothelin Receptor Antagonists
• Female
• Heart Rate (drug effects, physiology)
• Hemodynamics (drug effects, physiology)
• Hemoglobins (metabolism)
• Hypoxia (drug therapy, metabolism, physiopathology)
• 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 (metabolism)
• Renal Circulation (drug effects, physiology)
• Respiration (drug effects)
• Sildenafil Citrate
• Sulfones (pharmacology)
• Task Performance and Analysis
• Theophylline (pharmacology)
• Thiophenes (pharmacology)
• Vasoconstriction (drug effects, physiology)