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

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.

Impact of hypocapnia and cerebral perfusion on orthostatic tolerance.

We examined two novel hypotheses: (1) that orthostatic tolerance (OT) would be prolonged when hyperventilatory-induced hypocapnia (and hence cerebral hypoperfusion) was prevented; and (2) that pharmacological reductions in cerebral blood flow (CBF) at baseline would lower the 'CBF reserve', and ultimately reduce OT. In study 1 (n = 24; aged 25 ± 4 years) participants underwent progressive lower-body negative pressure (LBNP) until pre-syncope; end-tidal carbon dioxide (P ET , CO 2) was clamped at baseline levels (isocapnic trial) or uncontrolled. In study 2 (n = 10; aged 25 ± 4 years), CBF was pharmacologically reduced by administration of indomethacin (INDO; 1.2 mg kg(-1)) or unaltered (placebo) followed by LBNP to pre-syncope. Beat-by-beat measurements of middle cerebral artery blood flow velocity (MCAv; transcranial Doppler), heart rate (ECG), blood pressure (BP; Finometer) and end-tidal gases were obtained continuously. In a subset of subjects' arterial-to-jugular venous differences were obtained to examine the independent impact of hypocapnia or cerebral hypoperfusion (following INDO) on cerebral oxygen delivery and extraction. In study 1, during the isocapnic trial, P ET , CO 2 was successfully clamped at baseline levels at pre-syncope (38.3 ± 2.7 vs. 38.5 ± 2.5 mmHg respectively; P = 0.50). In the uncontrolled trial, P ET , CO 2 at pre-syncope was reduced by 10.9 ± 3.9 mmHg (P ≤ 0.001). Compared to the isocapnic trial, the decline in mean MCAv was 15 ± 4 cm s(-1) (35%; P ≤ 0.001) greater in the uncontrolled trial, yet the time to pre-syncope was comparable between trials (544 ± 130 vs. 572 ± 180 s; P = 0.30). In study 2, compared to placebo, INDO reduced resting MCAv by 19 ± 4 cm s(-1) (31%; P ≤ 0.001), but time to pre-syncope remained similar between trials (placebo: 1123 ± 138 s vs. INDO: 1175 ± 212 s; P = 0.53). The brain extracted more oxygen in face of hypocapnia (34% to 53%) or cerebral hypoperfusion (34% to 57%) to compensate for reductions in delivery. In summary, cerebral hypoperfusion either at rest or induced by hypocapnia at pre-syncope does not impact OT, probably due to a compensatory increase in oxygen extraction.