Factors that are known to play a role in the autoregulation of muscle blood flow are e.g. flow/pressure-related effects such as the myogenic response, metabolic vasodilators such as adenosine, and local hypoxia. Local hypoxia appears to function as a regional second messenger to redirect organ-specific blood flow to the area of greatest need, and thus, systemic hypoxia drives the fine-tuned local flow regulation in peripheral organs and the brain out of balance. One of the well-known extrapulmonary cardiovascular effects of hypoxia is NO-mediated peripheral vasodilation, which, after rapid ascension to high altitude, leads to systemic arterial hypotension, and subsequently, to compensatory increases in heart rates. However, hypoxia is also capable of causing peripheral vasoconstriction in resistance arterioles, by triggering the release of the vasoconstrictor endothelin-1 from endothelial cells. Importantly though, while NO exerts its vasodilatory effect predominantly on 1st and 2nd order arterioles, endothelin-1 vasoconstricts only pre-capillary arterioles, and, via pericytes, also directly controls capillary diameter. Via endothelin-1 release, hypoxia is therefore capable of directly controlling capillary conductance. The importance of maintaining perfusion pressure during hypoxic vasodilation to enable efficient capillary blood flow has been recently addressed. In our study, ephedrine and MK-4827 ambrisentan exerted ergogenic effects only when ephedrine concentrations were used at doses that were sufficient to raise pulmonary and mean arterial blood pressure in anesthetized rats. Sympathetic activation, such as triggered by ephedrine or methylphenidate, specifically constricts larger, low-order peripheral arterioles. It is therefore plausible that the sympathomimetic treatment used in this study directly counteracted hypoxiatriggered, NO-mediated vasodilation, thereby reversing arterial hypotension and preserving perfusion pressure on the skeletal muscle. Sympathetic activation and endothelin blockade should therefore synergize to improve capillary perfusion and thus, increase oxygen transport to the hypoxic muscle. Indeed, the observed increase in muscle blood flow and oxygenation in anesthetized rats, in the absence of changes to HbO2 suggests that the observed enhancement of exercise performance in awake animals is mediated by changes in flow, rather than by arterial oxygen content. The observed increase in ventilation rate after treatment with ephedrine has been reported, but since it had no apparent impact on blood oxygen concentrations, this effect may not carry ergogenic significance. It is well known that the mammalian cardiovascular system responds to hypoxemia with increased cardiac output, which can, to some degree, be succeeded by increased muscle blood flow. This mechanism is probably responsible for the immediate, steep increase in muscle blood flow that was seen in many animals, following the onset of hypoxia shown in Figure 2B. Both the apparent extrapulmonary effect of ambrisentan on muscle, and the interaction between pharmaceutically-induced and hypoxia-stimulated increases in peripheral blood flow, will be important future topics.