Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
J Appl Physiol (1985). 2012 Oct 15;113(8):1243-52. doi: 10.1152/japplphysiol.01622.2011. Epub 2012 Aug 16.
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.
身体机能下降是快速上升到高海拔地区后一个众所周知的后果。低氧性肺血管收缩（HPV）可能会限制心输出量和全身血流，从而阻止身体对快速上升的成功适应。我们假设通过内皮素阻断来增强茶碱的心率作用，同时逆转 HPV，可以提高高海拔地区的运动表现。雌性 Sprague-Dawley 大鼠接受以下组合治疗：1）茶碱，2）内皮素受体拮抗剂西他生坦/安贝生坦，和/或 3）磷酸二酯酶-5 抑制剂西地那非，并暴露于模拟高海拔（4267 米）或 12%氧气环境中。检查运动能力、外周血流量、血液动力学和肺漏。茶碱与内皮素阻断的联合治疗，但不是各自的单一化合物，可显著延长模拟高海拔条件下的疲劳时间。当茶碱与西地那非联合使用时，并未发现这种效果。茶碱和西他生坦或它们的组合都没有影响呼吸频率和血红蛋白氧饱和度。虽然在低氧环境下，茶碱显著增加肌肉血流量，西他生坦增加组织氧合，但联合治疗改善了这两个参数，但效果降低。在低氧环境下，与对照组相比，联合治疗（13.1±6.3 对 11.9±5.2mmHg）而非单一化合物显著增加肺动脉压，而平均动脉压不受影响。联合治疗对肺湿干重比没有影响。我们得出结论，心脏刺激剂和内皮素拮抗剂的同时给药可以部分逆转低气压低氧环境下身体机能下降的能力，而不依赖于改善血氧饱和度。
