In patients with chronic obstructive pulmonary disease (COPD) studied at rest, nifedipine releases hypoxic pulmonary vasoconstriction (HPV) and worsens gas exchange. During exercise, this drug lowers pulmonary hypertension, but the effects of this lower pulmonary vascular tone on ventilation-perfusion (VA/Q) relationships are still poorly understood. To analyze them, we determined the VA/Q distributions in eight patients with stable COPD (FEV1, 36 percent of predicted) at rest and during exercise (60 percent VO2 max), before and after nifedipine (20 mg sublingually). Nifedipine shifted to the right the pulmonary pressure-flow relationship (p less than 0.01) and increased the dispersion of the blood flow distribution at rest and during exercise (p less than 0.005). These observations strongly suggest that nifedipine released HPV under both conditions. However, even after releasing HPV by nifedipine, exercise distributed blood flow more homogeneously than at rest (p less than 0.05). Besides, exercise greatly decreased the overall degree of VA/Q mismatching (p less than 0.001) not only before but also after nifedipine. Thus, we postulate that most of the VA/Q improvement that exercise may induce in patients with COPD, as it is shown here, is due to improvement in the ventilation distribution. Interestingly, this VA/Q improvement was not paralleled by a significant decrease of P(A-a)O2. This apparent paradox could be explained by 20 percent of the actual P(A-a)O2 during exercise due to diffusion limitation, as assessed through the inert gas approach. Taken all together, these results help to better understand the mechanisms that govern pulmonary gas exchange during exercise in COPD.