Acetazolamide during acute hypoxia improves tissue oxygenation in the human brain

Low doses of the carbonic anhydrase inhibitor acetazolamide provides accelerated acclimatization to high-altitude hypoxia and prevention of cerebral and other symptoms of acute mountain sickness. We previously observed increases in cerebral O-2 metabolism (CMRO2) during hypoxia. In this study, we investigate whether low-dose oral acetazolamide (250 mg) reduces this elevated CMRO2 and in turn might improve cerebral tissue oxygenation (Pti(O2)) during acute hypoxia. Six normal human subjects were exposed to 6 h of normobaric hypoxia with and without acetazolamide prophylaxis. We determined CMRO2 and cerebral Pti(O2) from MRI measurements of cerebral blood flow (CBF) and cerebral venous O-2 saturation. During normoxia, low-dose acetazolamide resulted in no significant change in CBF, CMRO2, or Pti(O2). During hypoxia, we observed increases in CBF [48.5 (SD 12.4) (normoxia) to 65.5 (20.4) ml.100 ml(-1).min(-1) (hypoxia), P < 0.05] and CMRO2 [1.54 (0.19) to 1.79 (0.25) mu mol.ml(-1).min(-1), P < 0.05] and a dramatic decline in Pti(O2) [25.0 to 11.4 (2.7) mmHg, P < 0.05]. Acetazolamide prophylaxis mitigated these rises in CBF [53.7 (20.7) ml.100 ml(-1).min(-1) (hypoxia + acetazolamide)] and CMRO2 [1.41 (0.09) mu mol.ml(-1).min(-1) (hypoxia + acetazolamide)] associated with acute hypoxia but also reduced O-2 delivery [6.92 (1.45) (hypoxia) to 5.60 (1.14) mmol/min (hypoxia + acetazolamide), P < 0.05]. The net effect was improved cerebral tissue Pti(O2) during acute hypoxia [11.4 (2.7) (hypoxia) to 16.5 (3.0) mmHg (hypoxia + acetazolamide), P < 0.05]. In addition to its renal effect, low-dose acetazolamide is effective at the capillary endothelium, and we hypothesize that local interruption in cerebral CO2 excretion accounts for the improvements in CMRO2 and ultimately in cerebral tissue oxygenation during hypoxia. This study suggests a potentially pivotal role of cerebral CO2 and pH in modulating CMRO2 and Pti(O2) during acute hypoxia.