Abstract
Rapid ascent to high altitude causes illness and fatigue, and there is a demand for effective acute treatments to alleviate such effects. We hypothesized that increased oxygen delivery to the tissue using a combination of a hypertensive agent and an endothelin receptor A antagonist drugs would limit exercise-induced fatigue at simulated high altitude. Our data showed that the combination of 0.1 mg/kg ambrisentan with either 20 mg/kg ephedrine or 10 mg/kg methylphenidate significantly improved exercise duration in rats at simulated altitude of 4,267 m, whereas the individual compounds did not. In normoxic, anesthetized rats, ephedrine alone and in combination with ambrisentan increased heart rate, peripheral blood flow, carotid and pulmonary arterial pressures, breathing rate, and vastus lateralis muscle oxygenation, but under inspired hypoxia, only the combination treatment significantly enhanced muscle oxygenation. Our results suggest that sympathomimetic agents combined with endothelin-A receptor blockers offset altitude-induced fatigue in rats by synergistically increasing the delivery rate of oxygen to hypoxic muscle by concomitantly augmenting perfusion pressure and improving capillary conductance in the skeletal muscle. Our findings might therefore serve as a basis to develop an effective treatment to prevent high-altitude illness and fatigue in humans.
Highlights
A reduction in physical performance capacity and untimely fatigue are among the deleterious acute effects of rapid ascent to high altitudes
Rats that were dosed with the combination of ephedrine or methylphenidate and the endothelin receptor antagonist (ERA) ambrisentan ran significantly longer than controls under simulated high altitude, whereas those treated with single drugs did not
Both ephedrine and ephedrine combined with ambrisentan increased heart rates, Mean arterial pressure (MAP), Pulmonary arterial pressure (PAP), breathing rates, blood flow to the hind limb musculature, and normoxic oxygenation, but only the drug combination significantly increased muscle oxygenation in hypoxic air
Summary
A reduction in physical performance capacity and untimely fatigue are among the deleterious acute effects of rapid ascent to high altitudes. Abundant experimental work has been conducted to identify mechanisms to augment arterial oxygen content (CaO2) by inducing hematopoiesis and increasing the hematocrit to improve exercise capacity at high altitude, but with variable success [3,4,5]. The beneficial effects observed for these drugs have been attributed to a reduction in pulmonary arterial pressure, and/or an improved ventilation-perfusion-matching (V/Q) [6,7,8,9]. Our group showed previously that the combined dosing with theophylline and the endothelin receptor blocker sitaxsentan significantly increased exercise capacity of rats under simulated high altitude, whereas the single compounds did not [10]. Theophylline is a highly pleiotropic drug with both cardiostimulatory and vasodilatory properties, and it has remained unclear whether augmentation of arterial blood pressure was essential for the observed ergogenic effects of the combination treatment
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