The combination of theophylline and endothelin receptor antagonism improves exercise performance of rats under simulated high altitude
The combination of theophylline and endothelin receptor antagonism improves exercise performance of rats under simulated high altitude
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DOI：
10.1152/japplphysiol.01622.2011
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发表时间：
2012-10-01
影响因子：
3.3
通讯作者：
Schroeder, Thies
中科院分区：
文献类型：
--
作者：
Radiloff, Daniel R.;Zhao, Yulin;Schroeder, Thies
快速上升到高海拔的一个众所周知的后果是身体机能下降。肺血管收缩功能减退（HPV）潜在地限制了心输出量和全身血流量，从而阻止了对快速上升的成功适应。我们假设，茶碱的心率药理学增强，结合通过内皮素阻断逆转HPV，可以增加在高海拔地区的运动表现。雌性Sprague-Dawley大鼠接受1）茶碱、2）内皮素受体拮抗剂西他生坦/安立生坦和/或3）磷酸二酯酶-5抑制剂西地那非的组合治疗，并暴露于模拟高海拔（4，267 m）或12%氧气。检查运动能力、外周血流量、血流动力学和肺渗漏。茶碱和内皮素阻断剂的联合治疗，而不是各自的单一化合物，显着延长模拟高海拔下的疲劳时间。茶碱与西地那非合用时无此疗效。茶碱、西他生坦或两者合用均不影响呼吸频率和血红蛋白氧饱和度。而在缺氧条件下，茶碱显着增加肌肉血流量，和sitaxsentan增加组织氧合，组合改善这两个参数，但在减少的方式。在缺氧条件下，与对照组相比，联合治疗而非单一化合物显著提高了肺动脉压（13.1 +/- 6.3 vs. 11.9 +/- 5.2 mmHg），而平均动脉压未受影响。肺湿干重比不受联合给药的影响。我们的结论是，伴随给药的心脏兴奋剂和内皮素拮抗剂可以部分扭转低压缺氧下的体力劳动能力的损失，独立于改善血氧饱和度。
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.