Dissertation
Cardiopulmonary responses to hypoxia following inorganic nitrate supplementation
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2020
DOI: 10.17077/etd.005376
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.
Details
- Title: Subtitle
- Cardiopulmonary responses to hypoxia following inorganic nitrate supplementation
- Creators
- Joshua M Bock
- Contributors
- Darren P Casey (Advisor)Melissa L Bates (Committee Member)Vitor A Lira (Committee Member)Jason M Wilken (Committee Member)Richard K Shields (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Physical Rehabilitation Science
- Date degree season
- Spring 2020
- DOI
- 10.17077/etd.005376
- Publisher
- University of Iowa
- Number of pages
- xiii, 122 pages
- Copyright
- Copyright 2020 Joshua M Bock
- Language
- English
- Description illustrations
- illustrations
- Description bibliographic
- Includes bibliographical references (pages 86-122).
- Public Abstract (ETD)
The body reflexively increases respiration when blood oxygen levels fall and while vital to survival, exaggeration of this response can facilitate cardiovascular disease by increasing blood pressure. Older adults as well as those with obstructive sleep apnea have low levels of a key regulatory molecule of this reflex, nitric oxide, accompanied with an elevated response. Evidence shows supplementation with inorganic nitrate increases nitric oxide levels which may suppress the sensitivity of this reflex. Thus, the present research sought to determine if inorganic nitrate supplementation blunted the response to low oxygen levels in healthy older adults as well as in patients with obstructive sleep apnea. We demonstrate four-weeks of daily inorganic nitrate supplementation reduces the ventilatory response to low oxygen in healthy older adults which was accompanied by a reduction in blood pressure. Our second study illustrated a single dose of inorganic nitrate appears to blunt this response in patients with obstructive sleep apnea; however, these effects do not appear dose dependent. Additionally, data from this study suggest acute inorganic nitrate supplementation reduces the daytime rise in blood pressure of patients with obstructive sleep apnea. Collectively, these two studies highlight the beneficial effects of inorganic nitrate supplementation on blood pressure regulation with healthy aging as well as in patients with obstructive sleep apnea.
- Academic Unit
- Physical Therapy and Rehabilitation Science
- Record Identifier
- 9983949591902771
Metrics
30 File views/ downloads
65 Record Views