Upon exposure to low PO₂, the red blood cells of most species, including humans, release increased amounts of ATP which ultimately serves as a regulator of vascular tone matching oxygen supply with demand. In pathological conditions such as malaria and sepsis, a maldistribution of perfusion exists with its severity often correlated with the extent of elevation of serum lactate frequently in the absence of an alteration in pH. We hypothesized that the increased levels of lactate might impair the ability of the red blood cell to appropriately respond to conditions of low PO₂ thus preventing its important blood flow regulatory role. Using an in vitro system and rabbit red blood cells, we evaluated the capacity of cells incubated with lactate to release increased amounts of ATP in response to acute exposure to low PO₂. We found that in the presence of lactate, the red blood cells did not release ATP. However, when sodium dichloroacetate (DCA), a drug used clinically to lower blood lactate levels was added, ATP release was restored to levels which were not different from that of control cells (no lactate) even though intracellular levels of ATP were not. These results support the presence of a distinct, flow regulatory pool of ATP within the red blood cell which can be independently regulated and that lactate interferes with the ATP production within this pool thereby diminishing the amount of ATP available for release upon exposure to low PO₂. Therefore, if lactate levels can be reduced, the vascular regulatory capacity of the red blood cell should be restored thus enabling the appropriate matching of oxygen supply with oxygen demand.