Improvement of blood gases with the carbonic anhydrase inhibitor acetazolamide in some patients with chronic obstructive pulmonary disease (COPD) is believed to result from an effect on the ventilatory control system. Carbonic anhydrase is ubiquitously present within the body, particularly in tissues involved in the control of breathing. Because low inhibitor concentrations are sufficient to block the enzyme in many tissues, it is of interest to document the effect of clinical doses of acetazolamide on the CO(2) sensitivities of the peripheral and central chemoreflex loops. In this study we measured the effect of chronic acetazolamide (250 mg by way of mouth, every 8 h during 3 days) on the dynamic ventilatory response to step changes in end-tidal PCO(2) in nine healthy volunteers. Data were analyzed using a two-compartment model comprising a fast peripheral and slow central compartment, enabling us to separate drug effects on the peripheral and central chemoreflex loops, respectively. Compared with placebo, acetazolamide did not change the CO(2) sensitivities and time constants of both chemoreflex loops. However, mean (+/- SD) resting ventilation increased from 12.22 +/- 2.41 to 14.01 +/- 1.85 L. min(-1), resulting in a decrease in end-tidal PCO(2) from 40.0 +/- 4.7 to 33.3 +/- 3.5 mm Hg. Base excess decreased from -0.08 +/- 1.20 to -7.48 +/- 2.07 mmol. L(-1), indicating metabolic acidosis and explaining a leftward shift of the CO(2) response curve by 7.3 mm Hg. Possible clinical implications of these results are discussed.