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On the regulation of oxygen delivery to the brain in humans

University of British Columbia

Intact, coordinated, and precisely regulated increases in cerebral blood flow are required to compensate for reductions in arterial oxygen content and maintain cerebral oxygen delivery. This thesis aimed to determine the physiological processes and regulatory pathways that act to maintain cerebral oxygen delivery in humans and how these processes may be altered by long term exposure to hypoxia at evolutionary and pathological levels. Four studies were conducted to address these objectives. Study 1 investigated the influence of adenosine on the cerebral blood flow response to experimental hypoxemia at sea-level and high altitude. Compared to placebo treatment, adenosine receptor blockade had no impact on the cerebral blood flow response to acute or chronic hypoxemia indicating that adenosine is not an obligatory regulator of cerebral oxygen delivery. Study 2 was designed to determine the role of the erythrocyte in regulating cerebral blood flow and oxygen delivery during two forms of hypoxia: experimental hypoxemia and experimental anemia (hemodilution). The same overall reductions in arterial oxygen content elicited a more robust increase in cerebral blood flow and maintenance of cerebral oxygen delivery during hypoxemia than during hemodilution where cerebral oxygen delivery was reduced. Study 3 compared the regulation of cerebral blood flow and oxygen delivery between lowland natives, and high-altitude natives – the Sherpa – upon graded ascent to 5050m. Sherpa possessed consistently lower cerebral oxygen delivery. However, given their exceptional physical capacity at altitude, this result may indicate a reduced oxygen demand analogous to hypoxia tolerant animals. Study 4 examined the influence of pathological chronic hypoxia on the matching of cerebral blood flow (and therefore oxygen delivery) to metabolic demand in chronic obstructive lung disease patients. Alleviation of hypoxemia with oxygen therapy augmented the flow response to neural activation, indicating chronic hypoxia impairs the mechanisms regulating cerebral oxygen delivery. While signaling mechanisms remain difficult to disentangle in humans, the erythrocyte has emerged as integral to the regulation of cerebral oxygen delivery. Chronic hypoxia at an evolutionary level may lead to positive adaptations related to oxygen demand, whereas pathological chronic hypoxia reduces the capacity to augment flow and oxygen delivery during neural activation.

Text

2018-08-27

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/66937

Interdisciplinary Studies

University of British Columbia

UBCO

http://creativecommons.org/licenses/by-nc-nd/4.0/