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

.. bridge amp and PowerLab module. A pulse oximetry foot clip was applied to the
left hind limb 150 of the animal (MouseOx, Starr Life Sciences) to record arterial
hemoglobin oxygen saturation 151 (HbO2), and heart rate. The …
Introduction: 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. Methods: 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. Results: Combination treatment with theophylline and endothelin blockade, but not with the respective single compounds, significantly prolonged time run to fatigue 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 HbO2. 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 (PAP) compared to controls (13.1 ± 6.3 vs. 11.9 ± 5.2 mmHg) whereas mean arterial pressure (MAP) remained unaffected. Pulmonary wet-to-dry weight ratios were unaffected by combination treatment. Conclusion: 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.