Year: 2020
Type: dissertation
Study design: Clinical Trial
Abstract: When the partial pressure of arterial oxygen (PaO2) falls, the body reflexively increases respiration and sympathetic outflow via the peripheral chemoreflex. This requires a highly complex and coordinated effort between the carotid bodies, regions of the medulla and hypothalamus, as well as end effector organs such as the diaphragm. Anatomically, originating within glomus cells of the carotid bodies located bilaterally at the common carotid artery bifurcation, this response incorporates a myriad of signaling molecules. However, preclinical data suggests nitric oxide (NO) may have a prominent role. That is, NO administration in murine and feline models attenuates carotid sinus nerve discharge during hypoxia. Moreover, inhibition of NO via pharmacological agents has been shown to augment this response. Translationally, attenuation of NO bioavailability with advancing age or in certain pathologies (e.g., obstructive sleep apnea) may promote exaggeration of peripheral chemoreflex sensitivity and predispose these individuals to various cardiovascular diseases (e.g., hypertension). While the peripheral chemoreflex can influence blood pressure, the baroreflex is still the dominant regulatory mechanism. Interestingly, the peripheral chemo- and baroreflexes share inverse relationship with one another such that, exaggerated peripheral chemoreflex sensitivity is associated with impaired baroreflex sensitivity; both of which may be a consequence of reduced NO levels. Over the past decade, consumption of inorganic nitrate has been shown to augment NO bioavailability independent of its traditional endogenous pathways and may therefore have therapeutic potential. The objectives of research in Chapter 2 were firstly to determine if four weeks of daily inorganic nitrate supplementation blunts peripheral chemoreflex sensitivity in healthy older adults using a randomized, placebo-controlled crossover design. Given the relationship between peripheral chemo- and baroreflex sensitivities, we also quantified spontaneous cardiovagal baroreflex sensitivity. Findings from these experiments illustrate that four-weeks of inorganic nitrate supplementation blunts peripheral chemoreflex sensitivity in healthy older adults with a commensurate reduction in systolic blood pressure. These beneficial effects occurred independently of changes in spontaneous cardiovagal baroreflex sensitivity. Importantly, the healthy older adults studied had similar ventilatory responses to hypoxia as a young reference cohort and were not diagnosed with hypertension at the time of their enrollment. Collectively, these data show promise for improving blood pressure regulation in clinical populations with exaggerated peripheral chemoreflex sensitivity. In the second investigation (Chapter 3) we studied if the beneficial effects observed in Chapter 2 translated to patients with obstructive sleep apnea as they are known to have exaggerated peripheral chemoreflex sensitivity as well as reduced NO bioavailability. Using another randomized, placebo-controlled crossover design we studied if acute inorganic nitrate supplementation blunted the peripheral chemoreflex sensitivity and if the hypothesized effects were dose-dependent. We also measured common carotid artery blood flow as 1) cerebral perfusion may confound primary outcome measures and 2) inorganic nitrate supplementation augments blood flow particularly during hypoxia. Data collected during these studies suggests patients with obstructive sleep apnea experience a diurnal rise in systolic blood pressure as well as peripheral chemoreflex sensitivity and that inorganic nitrate blunts these observations; however, this was not dose dependent. Additionally, these beneficial effects do not appear to be influenced by changes in cerebral perfusion as there were no differences between placebo and either dose of inorganic nitrate. Collectively, these data suggest increasing NO bioavailability, acutely or over a period of weeks, can blunt peripheral chemoreflex sensitivity. Moreover, these beneficial effects are accompanied by favorable changes in systolic blood pressure. Interestingly, this appears to occur independently of changes in cardiovagal baroreflex sensitivity and cerebral perfusion.
DOI: 10.17077/etd.005376
Language: English
Subfield: Endocrine and Autonomic Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4254789224