Abstract
The extent to which systemic hypoxia may compromise cerebrovascular function is likely to depend on the intensity and duration of the hypoxic insult. This thesis presents four studies that used a range of intermittent and continuous hypoxic paradigms that examined i) whether hypoxia alters cerebrovascular reactivity during acute alterations in the partial pressure of end-tidal CO2 (PETCO2) and end-tidal O2 (PETO2); and ii) whether reductions in cerebrovascular reactivity were mediated by changes in nitric oxide (NO). As a secondary goal, the impact of alterations in peripheral chemoreceptor (PCR) activity on cerebrovascular function, and on ventilatory (VE) sensitivity were also explored. Blood flow velocity in the middle cerebral artery (MCAv) and cerebral oxygenation, provided indices of cerebrovascular function.
Study one demonstrated that acute hypercapnia was associated with the net release of NO from the brain. Therefore, in subsequent studies, cerebrovascular reactivity to hypercapnia, along with complementary NO metabolites (plasma nitrite and NOx [nitrite + nitrate]), was used as a surrogate index of NO bioavailability.
Study two examined the effects of chronic (years) intermittent hypoxia (CIH) on cerebrovascular function in patients with severe obstructive sleep apnoea (OSA, apnoea-hypopnoea index > 30 events/h). When compared to a group of appropriate controls, hypercapnic cerebrovascular reactivity was reduced in OSA patients. Since plasma NOx was also reduced, it would seem feasible that this compromise in reactivity was due to a reduction in NO bioavailability. Nevertheless, correlative analysis revealed that the presence of OSA was not the only factor associated with a reduction in hypercapnic cerebrovascular reactivity; a novel finding was that increased age and body mass index were linked as well. Alleviating CIH with 5-6 weeks of continuous positive airway pressure (CPAP) caused no alterations in hypercapnic cerebrovascular reactivity or NO metabolites, but caused a small (4 mmHg) reduction in mean arterial blood pressure (MABP).
Study three examined the effects of short-duration intermittent hypoxia [SDIH] and short-duration continuous hypoxia [SDCH]) on cerebrovascular function in healthy participants. For SDIH, participants performed 2 h of repetitive hypoxic apnoeas to mimic OSA (20 s apnoeas; nadir peripheral oxygen saturation [SpO2] ~84%; 30 times/h). For SDCH, participants were exposed to a single hypoxic episode matched in duration (i.e., 20 min) and intensity (i.e., SpO2) to SDIH. Cerebrovascular reactivity and ventilatory sensitivity were assessed during acute PETCO2 alterations under hyperoxic and hypoxic rebreathing in order to provide insight into PCR activity. SDIH (but not SDCH) led to a selective reduction in frontal cerebral oxygenation during hypoxic rebreathing; no concomitant alterations in MCAv or in NO metabolites were observed. One interpretation of these findings is that oxygenation of the frontal lobe was compromised to ensure perfusion of more vital regions of the brain (e.g., brainstem) after SDIH. SDCH (but not SDIH) led to elevations in MABP at rest and MABP reactivity during hypoxic but not hyperoxic rebreathing, likely mediated via PCR activation. No concomitant alterations in VE sensitivity during hypoxic rebreathing were observed possibly due to different rates of recovery for MABP and VE post SDCH; there were no alterations in VE sensitivity during hyperoxic rebreathing.
Lastly, in study four, the effect of ~3 weeks of continuous hypoxia on cerebrovascular function and ventilatory sensitivity was examined in healthy sea-level participants following ascent to 5050 m. The main findings were that ascent to 5050 m led to an increase in resting MCAv, and enhanced MCAv reactivity during hypoxic and hyperoxic rebreathing. Alongside a high-altitude induced increase in resting VE , these cerebrovascular responses might serve to maintain oxygen delivery to the brain in the face of hypoxia until other adaptive mechanisms (e.g., an increase in capillary density) that aid oxygen extraction become manifest.
Collectively, these findings indicate that the precise effect of systemic hypoxia on cerebrovascular function was contingent on the hypoxic paradigm. Shorter durations of hypoxia (i.e., 2 h intermittent hypoxia and ~3 weeks continuous hypoxia) evoke cerebrovascular responses that may serve to preserve oxygen delivery to vital regions of the brain whereas longer durations of intermittent hypoxia (i.e., CIH, in patients with OSA), is associated with a reduction in cerebrovascular function that may compromise brain function. Furthermore, the findings of this thesis suggest that: i) a reduction in NO bioavailability may contribute to a reduction in hypercapnic cerebrovascular reactivity in patients with OSA; and ii) that alteration in PCR activity may contribute to the elevated MABP after 2 h of continuous hypoxia. Irrespective of the hypoxic paradigm, the cerebrovascular, cardiovascular and ventilatory responses to acute alterations in PETCO2 and PETO2 are complex and inter-related.