Adenosine receptor dependent signaling is not obligatory for normobaric and hypobaric hypoxia-induced cerebral vasodilation in humans

Abstract

Hypoxia increases cerebral blood flow (CBF) with the underlying signaling processes potentially including adenosine. A randomized, double-blinded, placebo controlled design, was implemented to determine if adenosine receptor antagonism (theophylline, 3.75 mg/Kg) would reduce the CBF response to normobaric and hypobaric hypoxia. In 12 participants the partial pressures of end-tidal oxygen (PETO2) and carbon dioxide (PETCO2), ventilation (pneumotachography), blood pressure (finger-photoplethysmography), heart- rate (electrocardiogram), CBF (duplex ultrasound), and intra-cranial blood velocities (transcranial Doppler ultrasound) were measured during five-minute stages of isocapnic hypoxia at sea-level (98, 90, 80, & 70% SaO2). Ventilation, PETO2 and PETCO2, blood pressure, heart-rate and CBF were also measured upon exposure (128±31 minutes following arrival) to high-altitude (3800m) and six-hours following theophylline administration. At sea-level, although the CBF response to hypoxia was unaltered pre/post placebo, it was reduced following theophylline (P<0.01); a finding explained by a lower PETCO2 (P<0.01). Upon mathematical correction for PETCO2, the CBF response to hypoxia was unaltered following theophylline. Cerebrovascular reactivity to hypoxia (i.e. response slope) was not different between trials, irrespective of PETCO2. At high-altitude, theophylline (n=6) had no effect on CBF compared to placebo (n=6) when end-tidal gases were comparable (P>0.05). We conclude that adenosine receptor dependent signaling is not obligatory for cerebral hypoxic vasodilation in humans.