Lindsey M Boulet1, Luc J Teppema2, Heather K Hackett3, Paolo B Dominelli4, William Spencer Cheyne5, Giulio S Dominelli6, David C Irwin7, Paul W Buehler8, Jin Hyen Baek9, Erik Richard Swenson10, Glen Edward Foster11. 1. Health and Exercise Science, University of British Columbia. 2. Anesthesiology, Leiden University Medical Center, Netherlands. 3. School of Health and Exercise Sciences, University of British Columbia. 4. Mayo Clinic, United States. 5. University of British Columbia, Canada. 6. University of British Columbia. 7. Division of Cardiovascular Pulmonary Research, University of Colorado Denver Health Sciences Center, United States. 8. CBER, FDA, United States. 9. CBER, FDA. 10. Medicine, University of Washington, VA Puget Sound, United States. 11. School of Health and Exercise Science, University of British Columbia, Canada.
Abstract
RATIONALE: Acetazolamide, a carbonic anhydrase inhibitor used for preventing altitude illness attenuates hypoxic pulmonary vasoconstriction (HPV) while improving oxygenation. Methazolamide, 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. OBJECTIVE: To determine if a clinically relevant dosing of methazolamide improves oxygenation, attenuates HPV and augments plasma antioxidant capacity in men exposed to hypoxia when compared to an established dosing of acetazolamide known to suppress HPV. METHODS: In this double-blind, placebo-controlled, cross-over trial, eleven participants were randomized to treatments with methazolamide (100mg b.i.d.) and acetazolamide (250mg t.i.d.) for two days prior to 60 minutes of hypoxia (FIO2≈0.12). MEASUREMENTS: Pulmonary artery systolic pressure (PASP), alveolar ventilation (V̇A), blood gases and markers of redox status were measured. Pulmonary vascular sensitivity to hypoxia was determined by indexing PASP to alveolar PO2. RESULTS:Acetazolamide caused greater metabolic acidosis compared with methazolamide, but the augmented V̇A and improved oxygenation with hypoxia were similar. The rise in PASP with hypoxia was lower with methazolamide (9.0 ± 0.9 mmHg) and acetazolamide (8.0 ± 0.7 mmHg) compared with placebo (14.1 ± 1.3 mmHg; P < 0.05). The pulmonary vascular sensitivity to hypoxia (ΔPASP/ΔPAO2) was reduced equally by both drugs. Only acetazolamide improved the non-enzymatic plasma antioxidant capacity. CONCLUSIONS: Although acetazolamide only had plasma antioxidant properties, methazolamide led to similar improvements in oxygenation and reduction in HPV at a dose causing less metabolic acidosis than acetazolamide in humans.
RCT Entities:
RATIONALE: Acetazolamide, a carbonic anhydrase inhibitor used for preventing altitude illness attenuates hypoxic pulmonary vasoconstriction (HPV) while improving oxygenation. Methazolamide, 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. OBJECTIVE: To determine if a clinically relevant dosing of methazolamide improves oxygenation, attenuates HPV and augments plasma antioxidant capacity in men exposed to hypoxia when compared to an established dosing of acetazolamide known to suppress HPV. METHODS: In this double-blind, placebo-controlled, cross-over trial, eleven participants were randomized to treatments with methazolamide (100mg b.i.d.) and acetazolamide (250mg t.i.d.) for two days prior to 60 minutes of hypoxia (FIO2≈0.12). MEASUREMENTS: Pulmonary artery systolic pressure (PASP), alveolar ventilation (V̇A), blood gases and markers of redox status were measured. Pulmonary vascular sensitivity to hypoxia was determined by indexing PASP to alveolar PO2. RESULTS:Acetazolamide caused greater metabolic acidosis compared with methazolamide, but the augmented V̇A and improved oxygenation with hypoxia were similar. The rise in PASP with hypoxia was lower with methazolamide (9.0 ± 0.9 mmHg) and acetazolamide (8.0 ± 0.7 mmHg) compared with placebo (14.1 ± 1.3 mmHg; P < 0.05). The pulmonary vascular sensitivity to hypoxia (ΔPASP/ΔPAO2) was reduced equally by both drugs. Only acetazolamide improved the non-enzymatic plasma antioxidant capacity. CONCLUSIONS: Although acetazolamide only had plasma antioxidant properties, methazolamide led to similar improvements in oxygenation and reduction in HPV at a dose causing less metabolic acidosis than acetazolamide in humans.