Attenuation of human hypoxic pulmonary vasoconstriction by acetazolamide and methazolamide

Acetazolamide (AZ), a carbonic anhydrase inhibitor used for preventing altitude illness attenuates hypoxic pulmonary vasoconstriction (HPV) while improving oxygenation. Methazolamide (MZ), an analog of acetazolamide, is more lipophilic, has a longer half-life, and activates a major antioxidant transcription factor. However, its influence on the hypoxic pulmonary response in humans is unknown. The aim of this study was to determine whether a clinically relevant dosing of MZ improves oxygenation, attenuates HPV, and augments plasma antioxidant capacity in men exposed to hypoxia compared with an established dosing of AZ known to suppress HPV. In this double-blind, placebo-controlled crossover trial, 11 participants were randomized to treatments with MZ (100 mg 2× daily) and AZ (250 mg 3× daily) for 2 days before 60 min of hypoxia (F_IO₂ ≈0.12). Pulmonary artery systolic pressure (PASP), alveolar ventilation (V̇_A), blood gases, and markers of redox status were measured. Pulmonary vascular sensitivity to hypoxia was determined by indexing PASP to alveolar PO₂. AZ caused greater metabolic acidosis than MZ, but the augmented V̇_A and improved oxygenation with hypoxia were similar. The rise in PASP with hypoxia was lower with MZ (9.0 ± 0.9 mmHg) and AZ (8.0 ± 0.7 mmHg) vs. placebo (14.1 ± 1.3 mmHg, P < 0.05). Pulmonary vascular sensitivity to hypoxia (ΔPASP/ΔP_AO₂) was reduced equally by both drugs. Only AZ improved the nonenzymatic plasma antioxidant capacity. Although AZ had only plasma antioxidant properties, MZ led to similar improvements in oxygenation and reduction in HPV at a dose causing less metabolic acidosis than AZ in humans.NEW & NOTEWORTHY Both acetazolamide and methazolamide are effective in the prevention of acute mountain sickness by inducing an increase in ventilation and oxygenation. Acetazolamide attenuates hypoxic pulmonary vasoconstriction; however, it was previously unknown whether methazolamide has the same effect in humans. This study shows that a dosing of methazolamide causing less metabolic acidosis improves oxygenation while attenuating hypoxic pulmonary vasoconstriction and pulmonary vascular sensitivity to hypoxia. Acetazolamide improved plasma antioxidant capacity better than methazolamide.