Competing effects of arterial pressure and carbon dioxide on cerebrovascular regulation during exercise and orthostatic stress

Abstract

The human brain is highly sensitive to changes in cerebral blood flow. There are multiple integrated and redundant regulatory mechanisms acting simultaneously to ensure adequate cerebral perfusion and removal of waste products. However, the contribution of different cerebrovascular control mechanisms to the increase in cerebral blood flow during exercise or the reduction in flow during orthostatic stress are controversial, especially for the competing roles of arterial pressure and CO2. Therefore, the purpose of this thesis was to identify which regulatory factors play prominent roles in modulating cerebral blood flow during and following transitions in exercise intensity or posture change. This was accomplished through a series of experiments that evaluated cerebrovascular responses to moderate- and high-intensity interval exercise, bed rest, and orthostatic stress tests to pre-syncope. Through causal time-series modeling, it was identified that cerebral autoregulation effectively minimized the effects of exercise-induced increases in mean arterial pressure (MAP) on middle cerebral artery blood velocity (MCAv), and that changes in estimated arterial partial pressure of CO2 (PaCO2) largely dictated MCAv dynamics in response to step changes in work rate. These findings sharply contrast with recent attempts to characterize the increase in MCAv at the onset of exercise as a mono-exponential response. Sex-specific effects of MAP and end-tidal PCO2 on MCAv were identified while standing following two weeks of bed rest in post-menopausal women and similar-aged men, with reduced end-tidal PCO2 contributing to reductions in men and lower MAP contributing to reductions in women. Vertebral artery blood flow was also identified as an important factor potentially mediating cerebrovascular-respiratory interactions during orthostatic stress in the progression to syncope. Overall, the results of these experiments demonstrate important connections between the cerebral vasculature and respiratory control during exercise and orthostatic stress, enhancing our fundamental understanding of cerebrovascular control and the integrative cerebrovascular cascade leading to syncope.