Hypertension is a known effect of both of these drugs, and neither has been previously reported for their potential to mitigate altitude-related performance decrements. We hypothesized that the hypertensive drugs ephedrine or methylphenidate, when combined with an endothelin-1 blocking agent, would increase exercise performance under simulated high altitude in a rat model, whereas the single compounds would not. The proposed mechanism would involve an increased perfusion pressure in peripheral organs such as skeletal muscle, synergizing with a reduction of endothelin-mediated pre-capillary arteriolar vasoconstriction and leading to improved capillary flow and oxygen transport. We tested the novel hypothesis that combined dosing with a chronotropic, hypertensive drug and the endothelin receptor antagonist ambrisentan, under simulated high altitude, would produce a more distinct ergogenic effect than the single compounds alone. Indeed, rats that were dosed with the combination of ephedrine or methylphenidate and the endothelin receptor antagonist ambrisentan ran significantly longer than controls under simulated high altitude, whereas those treated with single drugs did not. In anesthetized rats, both ephedrine and ephedrine combined with ambrisentan increased heart rates, MAP, PAP, breathing rates, blood flow to the hind limb musculature, and normoxic oxygenation, but only the drug combination significantly increased BIBW2992 muscle oxygenation in hypoxic air. Several compounds have been suggested for the potential alleviation of altitude-induced fatigue, including inhibitors of phosphodiesterase type 5, dexamethasone, endothelin receptor antagonists, and erythropoietin pre-treatment. Of note, increasing hematocrit by “blood doping” has not been demonstrated to enhance performance capacity at high altitude. We recently reported that the combination of theophylline and the endothelin receptor antagonist sitaxsentan synergized to improve exercise performance of rats under hypobaric hypoxia, exceeding the effects of theophylline or sitaxsentan given alone. In addition, we showed that the improved exercise performance was due to increased blood flow to peripheral tissue, potentially driven and powered by the augmenting effect of theophylline on heart rate and arterial blood pressures. Subsequently, we have here investigated the effects of pharmacologically-induced hypertension in combination with endothelin blockade, using a rodent exercise model under simulated high altitude. Ephedrine is a naturally-occurring sympathomimetic amine that shares structural and functional similarity with amphetamine, as well as with the neurotransmitter epinephrine. Ephedrine directly activates alpha- and beta-adrenergic receptors, triggers catecholamine release, and inhibits norepinephrine reuptake. Physiologically, ephedrine increases heart rate, peripheral resistance and arterial pressure, and may cause hallucinogenic side effects. In addition to its medical use, ephedrine has been tried for many years as a performance-enhancing agent; however, consistent ergogenic effects are only achieved if combined with agents such as caffeine.