Effects of two carbonic anhydrase inhibitors on exercise performance in acute hypoxia

Acute mountain sickness (AMS) occurs due to rapid altitude ascents and/or insufficient acclimatization. Acetazolamide (AZ) is commonly prescribed for AMS prophylaxis but inhibits exercise performance. Methazolamide (MZ), an analogous drug, has similar prophylactic benefits but does not impair isolated muscle mass exercise performance in normoxia. We sought to compare whole body exercise performance in acute hypoxia (fraction of inspired oxygen, [Formula: see text] = 0.15) between AZ, MZ, and placebo (PLA). Fifteen healthy participants completed five testing visits: day 1 for maximal exercise test, day 2 for familiarization, and days 3-5 were the experimental visits. Each experimental visit involved a 5-km hypoxic cycling time trial (TT) performed after a 2-day dosing protocol of either AZ (250 mg three times a day), MZ (100 mg twice a day), or PLA (three times a day); the order was randomized and double-blinded. Before exercise, capillary blood samples were taken, and maximal voluntary contractions of quadriceps were performed. AZ and MZ resulted in a partially compensated metabolic acidosis at rest compared with PLA [capillary hydrogen ions (H⁺) 47 ± 3, 43 ± 2, and 39 ± 2 nmol for AZ, MZ, and PLA respectively, P < 0.01]. Time to complete 5 km with PLA (562 ± 32 s, P < 0.01) was significantly faster than AZ and MZ (577 ± 38 vs. 581 ± 37 s, respectively), with no differences between AZ and MZ (P = 0.96). There were no differences in average ventilation (124 ± 27, 127 ± 24, 127 ± 19 L/min) and oxyhemoglobin saturation (87 ± 2, 88 ± 2, 88 ± 3%) between AZ, MZ, and PLA, respectively (P > 0.05). Overall, both AZ and MZ impair whole body exercise performance in acute normobaric hypoxia.NEW & NOTEWORTHY Administration of acetazolamide (AZ) and methazolamide (MZ) both resulted in a significantly slower 5-km time trial in acute normobaric hypoxia compared with a placebo. Both drugs lead to a partially compensated metabolic acidosis, but ventilation and oxyhemoglobin saturation were not different across the conditions. Overall, acetazolamide and methazolamide both impaired whole body exercise performance in acute normobaric hypoxia but potentially have different mechanisms of action.