Abstract
Hypoxia increases cerebral blood flow (CBF) with the underlying signaling processes potentially including adenosine. A randomized, double-blinded, and 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 ([Formula: see text]) and carbon dioxide ([Formula: see text]), ventilation (pneumotachography), blood pressure (finger photoplethysmography), heart rate (electrocardiogram), CBF (duplex ultrasound), and intracranial blood velocities (transcranial Doppler ultrasound) were measured during 5-min stages of isocapnic hypoxia at sea level (98, 90, 80, and 70% [Formula: see text]). Ventilation, [Formula: see text] and [Formula: see text], blood pressure, heart rate, and CBF were also measured upon exposure (128 ± 31 min following arrival) to high altitude (3,800 m) and 6 h following theophylline administration. At sea level, although the CBF response to hypoxia was unaltered pre- and postplacebo, it was reduced following theophylline (P < 0.01), a finding explained by a lower [Formula: see text] (P < 0.01). Upon mathematical correction for [Formula: see text], the CBF response to hypoxia was unaltered following theophylline. Cerebrovascular reactivity to hypoxia (i.e., response slope) was not different between trials, irrespective of [Formula: see text] At high altitude, theophylline (n = 6) had no effect on CBF compared with 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.NEW & NOTEWORTHY The signaling pathways that regulate human cerebral blood flow in hypoxia remain poorly understood. Using a randomized, double-blinded, and placebo-controlled study design, we determined that adenosine receptor-dependent signaling is not obligatory for the regulation of human cerebral blood flow at sea level; these findings also extend to high altitude.
Highlights
NEW & NOTEWORTHY The signaling pathways that regulate human cerebral blood flow in hypoxia remain poorly understood
Hypoxia leads to an increase in blood velocity through the middle (MCA) and posterior (PCA) cerebral arteries [23, 45, 66], and an increase in blood flow through the internal carotid (ICA) and vertebral (VA) arteries, increasing global CEREBRAL BLOOD FLOW (CBF) [33]; this has been previously demonstrated to not occur until PaO2 has been reduced to a level below 59 mmHg [66]
Under placebo conditions Heart rate (HR) and V E increased at all stages of hypoxia pre- and postintervention while mean arterial pressure (MAP) increased at 90 and 70% hypoxia
Summary
NEW & NOTEWORTHY The signaling pathways that regulate human cerebral blood flow in hypoxia remain poorly understood. CEREBRAL BLOOD FLOW (CBF) increases in response to reductions in arterial oxygen content (CaO2) [9, 24, 30, 56] to maintain cerebral oxygen delivery (CDO2) in normobaric [3, 66] and hypobaric hypoxia [4, 26]. While the regulation of hypoxic cerebral vasodilation is complex and undoubtedly involves a multitude of signaling pathways (reviewed in Ref. 24), several factors are commonly recognized as the likely key mediators of this response. These include, but are not limited to nitric oxide [39], adenosine triphosphate [11], and adenosine [5, 70]. Posterior cerebrovascular reactivity to isocapnic hypoxia is reportedly greater than that of anterior cerebrovascular reactivity [66], it has yet to be investigated if regional differences in CBF regulation are attributable to adenosine
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