Open Collections

UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Intermittent hypoxia : cardiorespiratory and cerebrovascular consequences to acute hypoxia and submaximal.. Querido, Jordan S 2007

You don't seem to have a PDF reader installed, try download the pdf

Item Metadata

Download

Media
ubc_2007-0561.pdf [ 3.88MB ]
Metadata
JSON: 1.0077046.json
JSON-LD: 1.0077046+ld.json
RDF/XML (Pretty): 1.0077046.xml
RDF/JSON: 1.0077046+rdf.json
Turtle: 1.0077046+rdf-turtle.txt
N-Triples: 1.0077046+rdf-ntriples.txt
Original Record: 1.0077046 +original-record.json
Full Text
1.0077046.txt
Citation
1.0077046.ris

Full Text

INTERMITTENT HYPOXIA: CARDIORESPIRATORY AND CEREBROVASCULAR CONSEQUENCES TO ACUTE HYPOXIA AND SUBMAXIMAL EXERCISE  f  by  J O R D A N S. QUERIDO  B.Sc, The University of Ottawa, 2005  A THESIS SUBMITTED IN P A R T I A L F U L F I L L M E N T OF THE REQUIREMENTS FOR THE D E G R E E OF  M A S T E R OF SCIENCE in THE F A C U L T Y OF G R A D U A T E STUDIES ( H U M A N KINETICS)  THE UNIVERSITY OF BRITISH C O L U M B I A August, 2007  © Jordan S. Querido, 2007  ;  ABSTRACT Intermittent hypoxia (IH) is broadly defined as repeatedly breathing decreased amounts of oxygen (hypoxia) interspersed with periods of room air breathing (normoxia). In animal, human diseased, and healthy human models, research has shown IH to negatively affect cerebrovascular vessel dilation. We have previously shown poikilocapnic (uncontrolled carbon -dioxide (CO2)) IH to blunt the vasodilatory response of a cerebral vessel during acute hypoxia. The purpose of this study was to measure the ventilatory, cardiovascular and cerebrovascular responses to: I) acute hypoxia and; II) to submaximal exercise following an isocapnic (controlled " CO2) IH protocol. Healthy males (n = 9) with normal pulmonary function underwent 10 consecutive days of isocapnic IH (oxyhaemoglobin saturation (SaC^) = 80%, 1 hr/day).- " Ventilatory, cardiovascular, and cerebrovascular (transcranial Doppler) responses to acute -isocapnic hypoxia (Sa02 = 80%, 5 minutes) were measured before (PRE-IH) and after (POSTIH) IH. Also, ventilatory, cardiovascular, and cerebrovascular parameters were measured during a submaximal cycle exercise test (50, 100, 150 watts) PRE-IH and POST-IH. To further investigate cerebrovascular regulation during exercise, 5% CO2 was added for two minutes of each exercise stage. Over the 10 days of IH, there was a significant increase in minute ventilation ( V E ) during the IH bouts (p<0.05). IH did not significantly alter the ventilatory, cardiovascular, and cerebrovascular responses to acute hypoxia. However, there was a significant association (r = 0.86, p<0.05) between the change in the mean arterial blood pressure (MAP) and mean middle cerebral arterial blood flow velocity (MCAVm) responses to acute hypoxia. Exercise caused significant increases in V E , M C A V m , and M A P (p<0.05), but there were no differences in measured variables between PRE-IH and POST-IH exercise trials (p>0.05). Similarly, hypercapnia caused significant increases in V E and M C A V m (p<0.05), although the magnitude of the response did not change following IH. Our results suggest that the effect of IH on ventilatory, cardiovascular, and cerebrovascular regulation during acute hypoxia is ii  individualistic, and changes in the M A P response may strongly influence the changes in cerebral blood flow (CBF). Also, our results suggest that IH does not alter ventilatory, cardiovascular, or cerebrovascular regulation during submaximal exercise or responsiveness to hypercapnia.  TABLE OF CONTENTS ABSTRACT  ii  TABLE OF CONTENTS  iv  LIST OF TABLES  v  LIST OF FIGURES  vi  ACKNOWLEDGEMENTS  vii  INTRODUCTION  1  METHODS  7  RESULTS  13  DISCUSSION. REFERENCES  :  28 :  46  APPENDIX A - Review of Literature  58  APPENDIX B - Individual Raw Data  70  APPENDIX C - UBC Research Ethics Board's Certificate of Approval  78  iv  LIST OF TABLES Table 1. Subject characteristics  13  Table 2. Baseline ventilatory, cardiovascular, and cerebrovascular variables on PRE-IH and POST-IH test days  14  Table 3. Baseline variables throughout the 10 days of IH  14  Table 4. Measured variables during the 10 days of IH  16  Table 5. Change in ventilatory, cardiovascular and cerebrovascular variables from rest in response to the A H R  18  Table 6. Change in the ventilatory, cardiovascular and cerebrovascular response to acute hypoxia between the PRE-IH and POST-IH A H R tests  19  Table 7. Ventilatory, and cerebrovascular variables during exercise PRE-IH and POST-IH  24  Table 8. Cardiovascular variables during exercise PRE-IH and POST-IH  25  Table 9. Ventilatory, cardiovascular, and cerebrovascular variables during hypercapnic (5% carbon dioxide) rest and exercise  27  LIST OF FIGURES Figure 1. Middle cerebral arterial blood flow velocity ( M C A V ) response to acute progressive hypoxia before (A) and after (B) 10 consecutive days of intermittent hypoxia (12% O2 for 5 min, at 5 min intervals, for 1 hr/day) in one subject 3 Figure 2. Increase in ventilation from rest during IH over 10 days  15  Figure 3. Ventilatory, cardiovascular, and cerebrovascular response to acute hypoxia  Figure 4. A H R , V E  AHR cAVm, M  and A H R  M A P  PRE-IH and POST-IH  Figure 5. Association between the change in A H R M A P and A H R POST-IH  M  cAVm  17 20  between PRE-IH and 21  Figure 6. Ventilation ( V E ) , mean middle cerebral arterial velocity (MCAVm), and mean arterial blood pressure (MAP) in response to exercise and carbon dioxide (5% CO2) 23  vi  ACKNOWLEDGEMENTS I would like to express my appreciation to my supervisor, Dr. A . William Sheel, for his exceptional mentoring and guidance throughout my Master's degree. Many thanks also go to Drs. James Rupert and Donald McKenzie for serving on my thesis committee, and for providing valuable feedback throughout this project. I am grateful to my lab mates in the Health and Integrative Physiology Laboratory for their feedback and assistance on the study design, data collection, and data analysis of this project. Their friendly and supportive personalities really made the lab an enjoyable place to be. I am especially grateful to my family, who supported me and provided me with the means to pursue a career in research and academia. Lastly, I am extremely thankful to my lovely wife, Becky, for her continual support and patience.  Vll  INTRODUCTION Acute hypoxia causes abrupt increases in minute ventilation ( V E ) , mean arterial blood pressure (MAP), muscle sympathetic nerve activity ( M S N A ) , and cerebral blood flow (CBF) (7, 95). When hypoxia exposure becomes long-term or chronic, it initiates changes in other physiological parameters. Commonly experienced by mountaineers, residents of high-altitude, and athletes as part of an intensive high altitude training regimen, the effect of hypoxia also has many long-term ventilatory (54), cardiovascular (4), and haemotological (36) consequences. Indeed, the study of acute and chronic hypoxia has shown a diverse outcome to this type of environment; some of which can aid in athletic performance (72), others that can possibly be fatal (e.g. high altitude cerebral edema) (21). Hypoxia is particularly stressful on the brain, since cerebral tissue is intolerant of ischaemia; thus adequate CBF is essential. Traditionally, it was thought that CBF remained steady under all types of activity; however, there is clear evidence showing regional changes in CBF during different types of cerebral activity (e.g. mental stimulation, exercise) (58, 62). In general, CBF increases in response to hypoxia (48). This finding, although widespread, is affected by additional factors. Most notably, the confounding effect of carbon dioxide (CO2) which is a strong determinant of the effect of hypoxia on CBF (7). When CO2 is not controlled, poikilocapnic hypoxia has been shown to mask the increase in CBF, which is attributed to the hyperventilation induced hypocapnia (7). In fact, the responsiveness by cerebral vasculature to CO2 is of such significance, that CO2 is considered by many to be the major regulator of CBF (12). Similar to hypoxia, hypercapnia dilates cerebral vessels, resulting in an increase in CBF. A n increase in CO2 is thought to affect increases in cerebral vessel diameter by its simple diffusion through the blood brain barrier into the cerebrospinal fluid (CSF) (48). There, it dissociates into H and HCO3", after which H produces a relaxant effect on cerebral vessels. In +  +  contrast, hypocapnia (67), and possibly hyperoxia (11) cause decreases in CBF by 1  vasoconstriction of cerebral vessels. Collectively, cerebral chemoregulation refers to the dynamic maintenance of oxygen delivery, and adequate CO2 removal from cerebral tissue. It is important to note that hypoxia is commonly experienced in short, repeated bouts (e.g. sleep apnea); rather than a continuous exposure (e.g. residence at high altitude). The physiological magnitude that hypoxia patterning possesses has recently been appreciated (33, 112). Further, not only is hypoxic patterning of prime importance, but a key contributing factor, CO2, can influence the magnitude of the hypoxic response. In order to evaluate the effect of hypoxia, or IH, it is common to test the response to acute hypoxia. In general, IH causes increases in the AVe (33, 75, 78), A M A P (78), and A M S N A (95) response to acute hypoxia, while no change is observed in heart rate (HR) sensitivity (78). Recent research has shown rats that have been exposed to 10 days of repeated bouts of hypoxia (15s of 5% O2 at 5 minute intervals, 9 episodes/hr, 8hr/day) to have an increased carotid body sensitivity to acute hypoxia, when compared to rats who experienced less iterations in their hypoxic exposure (112). Further, IH has been shown to increase hypoxic M S N A in the human model, attributed to a greater burst frequency of the peroneal nerve (95). These results are in line with data in rats which show IH to cause an increase in daytime M A P (31, 78), although the causal relationship between M S N A and limb arteries is undefined (117). These findings extend to vessel function. Phillips et al. (113) investigated the effects of IH (Fi02 = 10% for one minute at four minute intervals, 12 h/day, 14 days) on isolated peripheral (gracilis artery) and cerebral (middle cerebral artery (MCA)) vessels in rats. Compared to control rats, the vasodilator response of both cerebral and peripheral vessels to a hypoxic bath was almost completely abolished. These findings have been substantiated in a diseased, human model. Sleep apnea is a condition defined by repetitive nightly apneas, thereby rendering the individual repeatedly hypoxic and hypercapnic. Sleep apnea patients are at a higher risk of many other ailments such as elevated daytime sympathetic nervous activity (20), hypertension (31), and stroke (26, 110). The typical IH that is experienced by this patient 2  population implies a key role of oxygen/reoxygenation for the increased risk of stroke (142). Foster et al. (32) found the CBF response to acute hypoxia to be reduced in sleep apnea patients when compared to healthy human controls. However, elimination of sleep apnea via continuous positive airway pressure normalized the CBF response in these patients (32). Also, we have shown data to support the key role of IH in the development of cerebral dysregulation in a healthy human model. Ten days of isocapnic IH attenuated cerebrovascular regulation, such that following IH there was a greater decrease in cerebral tissue oxygenation (near-infrared spectroscopy (NIRS)) for a given decrease in oxyhaemoglobin saturation (SaC^) during acute hypoxia (33). More recently, we extended these results by measuring CBF. We found that 10 consecutive days of poikilocapnic hypoxia attenuated the increase in CBF (transcranial Doppler ultrasonography) to acute hypoxia (Figure 1).  Figure 1. Middle cerebral arterial blood flow velocity ( M C A V ) response to acute progressive hypoxia before (A) and after (B) 10 consecutive days of intermittent hypoxia (12% O2 for 5 min at 5 min intervals, for 1 hr/day) in one subject. Each dot represents M C A V during a cardiac cycle.  0 0 : 0 0 : 0 0  0 0 : 0 5 : 0 0  0 0 : 1 0 : 0 0  0:00:00  Time (h:mm:ss)  0:05:00  0:10:00  Time (h:mm:ss)  Collectively, the results from animal, human diseased, and healthy human models have suggested the role of reactive oxygen species (ROS)  in the development of endothelial  dysfunction. It has been proposed that IH causes oxidative stress which in turn increases the  production of ROS. Excess production of ROS has been suggested to decrease the bioavailability of nitric oxide (NO), an endothelium-derived relaxing factor (113, 141). However, cerebral dysregulation following IH is not a universal finding. Kolb et al. (84) found an increase in the CBF response to acute hypoxia following five nocturnal hypoxic exposures ( F i 0 2 -13.8%). These results were recently supported by Ainslie et al. (2) who found the CBF response to acute poikilocapnic hypoxia to be augmented following 10-12 days of poikilocapnic IH ( F i 0 2 = 12% for 5 min at 5 min intervals, 90 min/day). Vessel dilation to hypoxia is partly mediated by the vasodilatory action of NO. Blitzer and colleagues (13) measured the effect of A^-monomethyl-L-arginine  (L-NMMA),  a NO  synthase antagonist, on forearm blood flow during hypoxia ( F i 0 2 = 13.9%). The administration of L - N M M A during hypoxia caused an approximate 34% decrease in forearm blood flow (13). Additionally, N O plays a key role in the vasodilation of cerebral vessels to hypercapnia (132). With the use of the same N O blocker ( L - N M M A ) , Iadecola (55) found the increase in CBF (rat brain) to hypercapnia (5% CO2) to be decreased by 44%, in comparison to hypercapnia alone. In the human model, individuals with endothelial dysfunction (e.g. diabetes mellitus, hypertension) also have a blunted vessel reactivity to hypercapnia (5% C O 2 ) , and infusion of a N O donor normalized the patients' reactivity. This study suggested the blunted C O 2 reactivity to be a consequence of an altered vascular endothelial production of NO (89). In addition to hypoxia and hypercapnia, CBF responds to other stimuli, which includes exercise. Although early reports provided somewhat inconsistent conclusions (39, 81, 131, 154), more recent evidence points to a clear increase in CBF to exercise (34, 49, 53, 70, 71, 93, 101, 115-117, 144). The increase is intensity dependent (70, 101), with the magnitude of the change contingent on the vessel insonated (49). Increases in exercise intensity cause an increase in CBF up to a certain exercise intensity (~60%VO2max), after which CBF decreases towards baseline values (sometimes decreasing below baseline values) with increasing exercise 4  intensity (49, 101). This is most likely attributed to a hyperventilation induced decrease in arterial partial pressure of C O 2 (PaCC^) (93, 101). Exercise results in an increase in blood flow to working muscles and the brain, increasing in shear stress on vessel endothelium. This shear stress initiates the release of NO, which in turn instigates vessel dilation (130). Inhibition of NO during exercise by infusion of L - N M M A greatly reduces exercising blood flow, suggesting a key role in vessel dilation during exercise to the release of NO by the endothelium (38). Similar to the CBF response to hypoxia, the regulation of CBF during exercise is strongly contingent upon the accompanying contribution of C O 2 . In fact, the typical increase in CBF during exercise can be completely abolished after correcting for the increase in end tidal partial pressure of carbon dioxide ( P E T C 0 ) (16). 2  Although we have shown IH to cause cerebral dysregulation to acute hypoxia at rest, this was shown to occur in an IH protocol where C O 2 was uncontrolled. Currently, the contribution of C O 2 during IH, whether it be isocapnic or poikilocapnic, is uncertain. In addition, recent reports have created discrepancy in the literature regarding the effects of IH on cerebrovascular regulation during acute hypoxia. Also, it is not known i f cerebrovascular dysregulation to acute hypoxia following IH persists under physiological conditions such as exercise. Most of the available literature suggests IH to cause vessel dysregulation, which is likely due to decreased bioavailability of NO, suggesting endothelial dysfunction. If these ideas can be extended to CBF during exercise, it may point to possible health risks for certain patient populations who undertake exercise programs, or healthy athletes who undergo IH as part of a high-altitude training regimen. The purpose of this study was twofold. First, we sought to determine i f 10 consecutive days of isocapnic IH would cause changes in the regulation of ventilatory, cardiovascular, and cerebrovascular variables to acute hypoxia. Second, we investigated the effect of the IH on the control of ventilatory, cardiovascular, and cerebrovascular variables during submaximal exercise. 5  Hypothesis It was hypothesized that in comparison to baseline, 10 days of isocapnic IH would result in: 1) A n increased V E , and M A P response to acute hypoxia, and a blunted C B F response to acute hypoxia 2) A blunted C B F response to submaximal exercise 3) A reduced C B F response to hypercapnia at rest and exercise  6  METHODS A l l experimental procedures and protocols were approved by the Clinical Research Ethics Board at the University of British Columbia which conforms to the Declaration of Helsinki. A l l testing procedures occurred in the Health and Integrative Physiology Lab on The University of British Columbia campus.  Subjects A total of nine males consented to participate in the study. Females were excluded from participation, as oscillations in female sex hormones throughout the menstrual cycle influence CBF and ventilatory control in hypoxic conditions (86, 126). A l l subjects were non-smoking, healthy individuals, in the low risk category for exercise as defined by the American College of Sports Medicine (8).  Experimental Protocol Each subject signed a consent form and filled out a Physical Activity Readiness Questionnaire, and underwent a familiarization session where all experimental procedures were completed. On a separate day, subject's response to acute hypoxia, submaximal exercise, and C O 2 reactivity was performed. Following the tests, subjects began the 10-day IH protocol. The day following the last IH session, subject's response to hypoxia, submaximal exercise and C O 2 reactivity were re-assessed as per Day 1.  Acute Hypoxic Response (AHR) Subjects performed the A H R while in a semi-recumbent position, in a quiet room, with minimal auditory and/or visual stimuli. Following instrumentation, subjects had a 10-minute rest period to ensure they were in a resting state. Next, Sa02 was decreased to 80% over an 7  approximate 2-3 minute time period by manual addition of N to the inspiratory circuit and 2  maintained for an additional 5 minutes. The test was maintained isocapnic (resting P E T C O 2 values for that day) by the manual addition of 100% C O 2 as needed. The measured variables were averaged during the last minute of rest, and the last minute of hypoxia; the absolute difference between the two was taken to represent the A H R for a given physiological variable (e.g acute hypoxic response of ventilation = A H R ) . VE  Exercise Protocol Identical exercise trials were performed in a normoxic environment on a semi-recumbent cycle ergometer (CombiCycle EX80, COMBI Corporation, Japan) one day prior to, as well as one day following the IH protocol. Subjects' feet were strapped to the pedals in order to maintain tight and constant contact as to minimize movement of the upper body. A five-minute rest period on the cycle ergometer preceded any exercise. A n average of all measured variables was taken during the last 30 seconds of rest and was used to represent baseline. Following the 5-minute rest period, C O 2 reactivity was measured at rest (described below). Following the C O 2 reactivity at rest, subjects were given one minute to recover. Next, subjects began pedaling at a constant rate to a metronome set at 60 Hz, and at a work rate of 50 watts (W); this workload was maintained for six minutes. Subsequent workloads were performed at the same cadence at 100 W and 150 W; each lasting six minutes. During exercise, C O 2 reactivity was tested over the fourth and fifth minutes at each workload. Measurements continued in recovery for 5 minutes following the last exercise intensity. This protocol was used in order to invoke a measurable increase in CBF, while minimizing subjects' head movement at higher intensities which would compromise the measurement of CBF.  8  CO2 Reactivity In order to test ventilatory, cardiovascular and cerebral C O 2 reactivity, subjects were administered a hypercapnic gas mixture (5% C O 2 , 21% O2, and 74% N2) via the inspired end of the non-rebreathing mouthpiece. Ventilatory, cardiovascular and cerebral C O 2 reactivity (e.g. ventilatory response to carbon dioxide = VECO2)  w e r e  assessed following the 5-minute rest  period, as well as during the fourth and fifth minute of each exercise intensity. Administration of the hypercapnic gas continued for a total of two minutes at each exercise intensity. The subjects were given a one-minute 'recovery' period following the administration of C O 2 before continuing on to the next stage.  Intermittent Hypoxia Intermittent hypoxia consisted of a one hour daily exposure where SaC^ measured with finger pulse oximetry (Criticare Systems Inc., 504 Series, Waukesha, WI) was maintained at 80%, for 10 consecutive days. Nitrogen was titrated into the inspired end of a non-rebreathing facemask in order to maintain Sa02 at 80%. Isocapnia was maintained by the manual addition of 100% C O 2 as needed. Subjects completed the intermittent hypoxia sessions in a sitting position, and were free to use computers, watch movies, or read throughout the session. We have previously shown similar IH protocols to cause changes in ventilatory, cardiovascular, and cerebrovascular variables during acute hypoxia (33, 95).  Cerebral Blood Flow Velocity Cerebral blood flow velocity (CBFV; an indication of cerebral blood flow) was measured throughout the pre- (PRE-IH) and post-testing (POST-IH) sessions with a 2 M H z pulsed Transcranial Doppler ultrasound (Neurovision, Multigon Industries Inc., Yonkers, N.Y.). C B F V was calculated from the maximal frequency of the Doppler shift, which is assumed to represent 9  the mean velocity in the centre of the vessel. The middle cerebral artery was insonated via the temporal window, directly superior to the zygomatic arch. The ultrasound probe was held in place with the use of a fixation head frame (Marc 600, Spencer Technologies, Seattle, WA) in order to maintain the position and angle of insonation throughout testing. Ultrasound gel (Aquasonic 100, Parker Laboratory Inc., Fairfield, New Jersey) was applied to the subjects' skin as well as the ultrasound probe before the experimenter located the segment of the middle cerebral artery to be insonated. The ultrasound probe was placed by the experimenter and adjusted by varying the angle and position of the ultrasound probe. Once a satisfactory signal was obtained, an outline of the subjects' ear, eye, mouth, and the placement of the probe was traced on a transparency film and used as a guideline for probe placement after IH (POST-IH). Ultrasound gel was then re-applied to the area of insonation and on the ultrasound probe, and the probe was placed in the ultrasound probe head fixation device. The experimenter re-located the area of the M C A insonated by decreasing the sample volume depth (originally at 6.0 cm) in incremental steps (0.1 cm), while varying the insonation angle at each step to obtain the best quality signal (121). The step-wise decrease in sample volume depth continued until the signal quality decreased. The lowest depth with an optimal Doppler signal was used for experimentation. A n average of the last 30 seconds of the third minute at each exercise intensity was used to represent CBF for that exercise stage. Placement of the Doppler probe was conducted by the same investigator (J. S. Querido) for all tests, and the protocol used to find the M C A was identical to search techniques used by other laboratories (121).  Ventilatory Parameters Inspiratory flow was recorded throughout experimentation and obtained using a heated pneumotach connected to the inspired side of a mouthpiece (AHR and exercise) and nasal breathing facemask (intermittent hypoxia). The mouthpiece replaced the mouth and nasal 10  breathing facemask during exercise in order to maintain a tighter seal around the mouth without obstructing placement of the Doppler probe. Inspiratory flow signals were integrated to determine volume and then multiplied by breathing frequency to obtain inspired minute ventilation. Inspired and expired fractions of oxygen (O2) and C O 2 were continuously monitored (O2: S-3A/I; C O 2 : CD-3A, AEI Technologies Applied Electrochemistry, Pittsburgh, Pennsylvania).  Cardiovascular Parameters Beat-by-beat systolic blood pressure (SBP), diastolic blood pressure (DBP), M A P , cardiac output (Q), as well as stroke volume (SV) were obtained throughout all experimentation by using finger pulse photoplethysmography (Finometer, Finapres Medical Systems, Arnhem, the Netherlands). Heart rate (HR) was calculated off-line from the arterial blood pressure trace. Prior to testing with the finger pulse photoplethysmograph, a return-to-flow systolic calibration was performed and the hydrostatic height sensor system was zeroed. The arm used to obtain blood pressure was placed on a platform at heart level in order to ensure the arm remained relaxed throughout testing.  Data and Statistical Analysis A l l variables were sampled at 100 Hz using an analog-to-digital data acquisition system (Powerlab/16SP model ML795, ADIInstruments, Colorado Springs, CO) and analyzed with commercially available software (Chart V5.02, ADInstruments, Colorado Springs, CO). Paired ttests were conducted to assess any changes is baseline physiological measures on the PRE-IH and POST-IH experimental days. IH. A one-way repeated measures A N O V A was conducted for each variable over the 10 days of IH to asses the effect of IH on baseline variables. Also, a one-way repeated measures 11  A N O V A was conducted on measured variables during the IH sessions (averaged over the last 55 minutes of each session). Investigation into the change (from normoxic rest to IH) in all measured variables during the IH over the 10 days was also done through the use of a one-way repeated measures A N O V A . If the test showed statistical significance, a Dunnett test was conducted to further investigate where (on which day) the difference occurred. AHR. The possible effect of IH on the A H R was investigated with a paired samples ttest. A Pearson product-moment was implemented to determine the relationship between selected variables during the PRE-IH A H R , POST-IH A H R , and the difference between PRE-IH to POST-IH. Exercise. A one-way repeated measures A N O V A was used in the PRE-IH, as well as the POST-IH exercise trials to investigate the effect of exercise intensity on measured variables. When the statistical test revealed significance, a Tukey's post hoc analysis was performed to investigate where the difference occurred. 2 (PRE-IH/POST-IH) X 9 (exercise intensity) repeated measures A N O V A was utilized to investigate any effect of IH on exercising variables. CO2 reactivity. One-way repeated measures A N O V A s were used to investigate the effect of hypercapnia on measured variables during the PRE-IH, and POST-IH trials. In order to investigate the difference between room air and hypercapnia in the PRE-IH and POST-IH trials, a one-way repeated measures A N O V A was conducted at each exercise intensity. A l l data are presented as mean ± SD. A level of significance of .05 was set for all statistical analyses.  12  RESULTS Subject Characteristics There was 100% compliance by subjects but one subject only completed 12 minutes of the second intermittent hypoxia session due to sensations of presyncope. Subjects' characteristics and spirometry values are presented in Table 1. A l l subjects were young, of normal height and weight. Seven of the nine subjects had BMI's within the normal range (18.5-24.9 kg/m ), 2  whereas two subjects had BMI's in the overweight range (25.0-29.9 kg/m ). Nonetheless, none of the subjects BMI's would have been considered in the obese range.  Table 1. Subject characteristics. BMI = body mass index; F V C = forced vital capacity; F E V i = forced expiratory volume in 1 second 0  Age (yrs) Height (cm) Mass (kg) BMI (kg/m ) 2  F V C (L) FEVLO (L) FEVLO/FVC (%) FEV  1 0  /FVC  (% predicted)  23.6 180.6 77.2 23.6 5.4  ±  +  2.4 6.6 10.4 2.0 0.9  4.5  +  0.6  83.5  +  4.9  98.4  +  5.7  + + +  Effect of IH on Baseline Physiological Measures Between the two experimental days, there were no significant differences in resting physiological measures; furthermore, there were no significant differences between resting measures before the A H R and exercise tests (Table 2). Inevitably, there was minor day-to-day variability, although it was not in excess of what was expected or reported by others (2, 120). Evaluation of the impact of IH on baseline ventilation revealed that although PRE-IH ventilation (9.5 ± 1.7 L/min) was slightly higher than baseline ventilation POST-IH (8.4 ± 2.1 L/min), the difference did not reach statistical significance (t(8) = 1.33, p>0.05). Likewise, there was no difference in baseline P E T C 0 between PRE-IH and POST-IH (t(8) = 0.05, p>0.05). M C A V m 2  13  was not statistically different on experimental days (t(8) = -1.45, p>0.05), nor were differences detected in baseline M A P (t(8) = -.07, p<0.05), HR (t(8) = .38, p>0.05), SV (t(8) = -.24, p>0.05), or Q (t(8) = .23, p>0.05) between experimental days.  Table 2. Baseline ventilatory, cardiovascular, and cerebrovascular variables on PRE-IH and POST-IH test days. V E = minute ventilation; PETCO2 = end tidal partial pressure of carbon dioxide; M C A V m = mean middle cerebral arterial velocity; SV = stroke volume; H R = heart rate; Q = cardiac output; Sa02 = oxyhaemoglobin saturation. VE (L/min) P E T C 0 (mmHg) 2  MCAVm (cm/s) MAP (mmHg) SV(ml) HR(bpm) Q (L/min) SaOz (%)  PRE-IH 9.5 + 1.7 42.3 + 2.2 64.2 + 8.6 92.4 + 5.8 102.6 + 18.9 61.2 + 9.4 6.2 ± 1.2 97.8 + 0.6  POST-IH 8.4 + 3.3 42.3 + 3.0 65.8 + 10.4 92.6 + 7.4 103.7 ± 22.6 60.5 + 10.8 6.2 + 1.3 97.8 + 0.7  CV (%) 19.4 + 14.4 3.0 + 1.8 2.7 + 2.5 4.4 + 2.3 7.7 + 6.9 5.7 + 3.1 6.5 + 5.4 0.3 + 0.2  Intermittent Hypoxia Intermittent hypoxia did not cause any significant change in baseline variables throughout the 10 days of IH (Table 3).  Table 3. Baseline variables throughout the 10 days of IH. V E = minute ventilation; PETCO2 = end tidal partial pressure of carbon dioxide; M A P = mean arterial blood pressure; S V = stroke volume; HR = heart rate; Q = cardiac output VE  Day Day Day Day Day Day Day Day Day Day CV  1 2 3 4 5 6 7 8 9 10 (%)  L/min 11.1 ± 3.7 11.5 ± 1.8 12.7 ± 3.9 12.2 ± 1.7 13.6 ± 2.6 13.3 ± 2.4 13.4 ± 2.1 13.0 ± 2.1 11.4 ± 1.9 12.5 ± 3.5 20.9 ± 7.8  PETC0  2  mmHg 40.3 + 1.7 40.8 ± 2.3 40.2 ± 2.9 39.7 ± 3.3 40.8 ± 2.9 38.9 ± 3.3 39.9 ± 2.2 39.9 ± 2.9 39.3 ± 2.3 38.5 ± 3.9 4.5 ± 2.3  MAP  mmHg 94.2 ± 4.0 92.3 ± 7.9 94.3 ± 9.3 91.9 ± 9.2 95.5 ± 7.2 94.0 ± 7.3 95.5 ± 3.0 95.2 ± 6.2 92.3 ± 6.4 89.6 ± 7.4 5.7 ± 1.8  SV  ml 92.7 ± 91.0 ± 89.1 ± 94.1 ± 97.3 ± 92.4 ± 90.8 ± 91.4 ± 88.8 ± 94.5 ± 12.2 ±  22.1 19.7 16.1 20.9 22.4 25.8 17.1 17.4 17.4 19.5 2.8  HR bpm 67.4 ± 12.6 64.8 ± 11.8 72.4 ± 1 1 . 5 68.7 ± 8.8 71.3 ± 11.4 67.9 ± 9.0 72.1 ± 10.1 69.1 ± 11.4 66.1 ± 5.8 64.5 ± 9.4 10.9 ± 2.5  Q  L/min 6.1 ± 1.4 5.9 ± 1.6 6.5 ± 1.6 6.4 ± 1.5 6^8 ± 1.7 6.3 ± 1.9 6.5 ± 1.5 6.3 ± 1 . 6 5.8 ± 1.1 6.1 ± 1.5 16.3 ± 6.1  14  As a group, the average SaC>2 experienced throughout the intermittent hypoxia sessions (excluding the first five minutes as SaCh was gradually decreased) was 80.8 ± 1.6 % (Table 4). Most subjects watched movies during the IH, while the rest of the sessions subjects read. Subject's P E T C O 2 during hypoxia was tightly regulated to the daily P E T C O 2 obtained at rest. Decreasing subject's SaCh to 80% caused an increase in V E ; V E progressively increased throughout the IH protocol (Figure 2). In contrast, the difference between rest and hypoxia did not change over the course of the IH in any other variable.  Figure 2. Increase in ventilation from rest during IH over 10 days. Data is presented as mean ± SE.  6  0  5-  r = 0.65,p<0.05  0  10 2  3  4  6  5  7  8  9  10  Day  15  Table 4. Measured variables during the 10 days of IH (data is an average from the last 55 minutes of each IH session). V E = minute ventilation; SaC>2 = oxyhaemoglobin saturation; PETCO2 = end tidal partial pressure of carbon dioxide; FiC>2 = fraction of inspired oxygen; M A P = mean arterial blood pressure; SBP = systolic blood pressure; DBP = diastolic blood pressure; HR = heart rate; SV - stroke volume; Q = cardiac output. V E (L/min)  S a Q (%)  Day1  13.3 ± 1.8  79.9 ± 0.9  Day2  15.6 ± 2.1  81.0 ± 2 . 0  41.1 ± 1.8  Day Day Day Day Day Day Day Day  14.1 14.4 15.9 15.9 16.1 17.5 17.0 17.0 16.2  81.8 80.7 81.1 80.4 80.9 80.8 81.1 81.1 1.7  40.5 40.6 41.4 40.6 40.7 40.6 40.1 40.1 3.2  3 4 5 6 7 8 9 10 C V (%)  ± 1.9 ± 2.4 ± 4.6 ± 3.3 ± 2.0 ± 3.6 * ± 2.0 * ± 2.0* ±4.7  2  ±2.1 ± 1.2 ± 0.9 ± 1.3 ± 1.7 ± 1.5 ± 1.8 ± 1.8 ±0.5  P E T C Q (mmHg) M A P (mmHg) 2  41.2 ± 1.1 ± ± ± + ± ± ± ± ±  2.6 2.3 2.5 2.5 2.0 2.4 2.4 2.4 0.8  99.6 ± 6.5 98.7 ± 8.0 101.3 ± 101.6 ± 100.8 ± 100.4 ± 101.9 + 101.2 ± 100.8 ± 100.8 ± 4.6 ±  8.8 8.2 4.5 5.5 4.8 6.4 3.5 3.5 2.7  MR (bpm)  SV(ml)  Q (L/min)  77.7 + 14.6  96.8 ± 24.0  7.4 ± 2.0  77.5 + 11.3  96.5 ± 11.6  7.5 ± 1.4  79.3 77.1 77.0 76.5 83.8 80.8 81.1 81.1 9.4  ± 12.4 97.6 ± 15.9 + 9.8 102.8 + 20.0 + 10.7 96.3 ± 2 1 . 6 ± 7.6 99.8 ± 19.5 ± 9.8 99.4 ± 10.9 + 11.4 95.1 ± 13.6 + 18.0 98.3 ± 19.1 + 18.0 98.3 ± 19.1 ± 4.7 8.9 ± 3.4  7.7 7.9 7.3 7.6 7.4 7.6 7.0 8.3 20.1  ± 1.6 ± 1.6 ± 1.7 ± 1.5 ± 3.0 ± 1.3 ± 3.2 ± 1.7 ± 15.0  * significantly different from Day 1  Acute Hypoxic Response For each individual subject, both the PRE-IH and POST-IH A H R were performed at the same time of day. As a group, mean Sa02 on both experimental days during the 5-minute A H R was 79.6 ± 1.6 %, which took an average of 3.1 ± 1.1 minutes to reach. A n average Fi02 of 11.4 ± 0.1% was required to evoke the appropriate drop in Sa02. Figure 3 displays the typical response during a PRE-IH acute hypoxic response.  16  Figure 3. Ventilatory, cardiovascular, and cerebrovascular response to acute hypoxia. Dashed lines are baseline, shaded area represents rest prior to the AHR. Sa02 = oxyhaemoglobin saturation; Fi02 = fraction of inspired oxygen; V E = minute ventilation; PETCO2 = end tidal partial pressure of carbon dioxide; M C A V m = mean middle cerebral arterial velocity; M A P = mean arterial blood pressure; Q = cardiac output. 1 0 0  -!_  r  30  9 0  8 5  -25  8 0  I  6 0  - 15  E 0 0 LL  E  7 5  7 0  > <  -10  6 5  - 5  0 2 2  8 0  0  OIAI  o  'in  -20  6 0  -,  2 0  A nl  1 8  x  1 6  E E. q_ <  1 4  1 2  H  VI  1 0  6  8 5  6 0 - i  1 2  n  5 0  x  1 0  E  8  I  40  9  i -  2  4  Time (min)  6  2  4  Time (min)  PRE-IH, V E significantly increased during the A H R from 9.5 ± 1 . 7 L/min at rest to 15.5 ± 1.8 L/min during acute hypoxia (t(8) = -7.7, p<0.05) (Table 5); similarly, the POST-IH A H R caused significant increases in V E from rest (8.4 ± 2.1 L/min) to hypoxia (16.1 ± 3.3L/min). Significant increases in systolic middle cerebral arterial velocity (MCAVs) (Pre-IH: t(8)=-2.38, p<0.05; Post-IH: t(8)=-2.67, p<0.05), H R (Pre-IH: t(8)-8.04, p<0.05; Post-IH: t(8)=-6.63, 17  p<0.05), and Q (Pre-IH: t(8)=-9.93, p<0.05; Post-IH: t(8)=-5.41, p<0.05) were also noted. The PRE-IH A H R did not cause an increase in diastolic middle cerebral arterial velocity (MCAVd), although significant increases in M C A V d occurred Post-IH (t(8)=-3.34, p<0.05).  Table 5. Change in ventilatory, cardiovascular and cerebrovascular variables from rest in response to the AHR. V E = ventilation; SaC^ = oxyhaemoglobin saturation; PETCO2 = end tidal partial pressure of carbon dioxide; FiC>2 = fraction of inspired oxygen; M C A V m = mean middle cerebral arterial velocity' M C A V s = systolic middle cerebral arterial velocity; M C A V d = diastolic middle cerebral arterial velocity; M A P = mean arterial blood pressure; SBP = systolic blood pressure; DBP = diastolic blood pressure; SV = stroke volume; H R = heart rate; Q = cardiac output • VE (L/min) Sa0 (%) 2  P E T C 0 (mmHg) 2  Fi0 (%) 2  MCAVm (cm/s) MCAVs (cm/s) MCAVd (cm/s) MAP (mmHg) SBP (mmHg) DBP (mmHg) SV (ml) HR (bpm) Q (L/min)  . rest 80% rest 80% rest 80% rest 80% rest 80% rest 80% rest 80% rest 80% rest 80% rest 80% rest 80% rest 80% rest 80%  Pre-IH 9.5 + 1.7 15.5 + 1.8 * 97.8 + 0.6 79.8 + 1.7 42.3 + 2.2 41.9 + 1.8 20.7 + 0.1 11.4 + 0.8* 64.2 ± 8.6 68.1 + 14.9 105.9 + 11.1 113.5 + 16.5* 41.6 + 6.7 44.3 + 10.7 92.4 + 5.8 94.1 + 7.3 126.8 + 7.0 130.7 + 6.6 74.3 + 7.1 75.3 + 7.1 102.6 + 18.9 102.1 + 18.2 61.2 + 9.4 75.7 + 11.3* 6.2 + 1.2 7.6 + 1.4*  Post-IH 8.4 + 2.1 16.1 + 3.3' 97.8 + 0.7 79.4 + 1.6 42.3 + 3.0 41.7 + 3.4 20.7 + 0.2 11.3 + 1.0* 65.8 + 10.4 69.5 + 12.2 107.8 + 15.1 113.2 + 16.1 43.3 + 7.5 46.6 + 9.0 92.6 + 7.4 94.3 + 7.4 127.7 + 6.1 131.8 + 7.3 74.7 + 9.3 76.1 + 9.0 103.7 + 22.6 102.4 + 24.5 60.5 + 10.8 73.2 ± 10.3 6.2 + 1.3 7.4 + 1.8* 1  * significantly different from P R E - I H rest significantly different from P O S T - I H rest  1  As a group, the  AHR E V  increased P O S T - I H (7.6 ± 4.4 L/min,) when compared to P R E - I H  (5.9 ± 2.3 L/min, t(8)=-1.20, p<0.05), although this did not reach statistical significance (Table  18  6). Individually, five of the nine subjects experienced an increased  Post-IH; four of the  AHRVE  nine subjects displayed a decrease (Figure 4). No significant difference in M C A V m was detected between the PRE-IH A H R (3.9 ± 9.2 cm/s) and POST-IH A H R (3.7 ± 3 . 7 cm/s, t(8)=.07, p>0.05); although five of the subjects experienced a decreased  AHR cAVm M  response during the  POST-IH A H R compared to the PRE-IH A H R . Similarly, there was no significant difference between the PRE-IH  A H R  M  A  P  (1.7 ± 6.2 mmHg) and the POST-IH  AHR  M  A  p  (1-8 ± 4.5, t(8)=-  0.05, p>0.05); although, four of the nine subjects experienced a decrease in the POST-IH AHRMAP  compared to the PRE-IH  AHRMAP,  whereas five of the subjects showed an increase.  Table 6. Change in the ventilatory, cardiovascular and cerebrovascular response to acute hypoxia between the PRE-IH and POST-IH A H R tests. V E = ventilation; S a 0 = oxyhaemoglobin saturation; PETCO2 = end tidal partial pressure of carbon dioxide; Fi02 = fraction of inspired oxygen; M C A V m = mean middle cerebral arterial velocity' M C A V s = systolic middle cerebral arterial velocity; M C A V d = diastolic middle cerebral arterial velocity; M A P = mean arterial blood pressure; SBP = systolic blood pressure; DBP = diastolic blood pressure; SV = stroke volume; HR = heart rate; Q = cardiac output 2  VE (L/min) Sa0 (%) P E T C 0 (mmHg) Fi0 (%) MCAVm (cm/s) MCAVs (cm/s) MCAVd (cm/s) MAP (mmHg) SBP (mmHg) DBP (mmHg) SV (ml) HR (bpm) Q (L/min) 2  2  2  Pre-IH 5.9 + -18.1 + -0.4 + -9.3 + 3.9 + 7.5 + 2.7 + 1.7 + 3.8 + 1.0 + -0.5 + 14.5 + 1.4 +  2.3 1.8 0.9 0.8 9.2 9.5 8.0 6.2 8.7 4.9 5.6 5.4 0.4  Post-IH 7.6 + 4.4 -18.3 + 1.7 -0.8 + 1.4 -9.3 ± 1.1 3.7 + 3.7 5.4 + 6.1 3.3 + 2.9 1.8 + 4.5 4.1 + 6.5 1.4 + 4.3 -1.4 + 5.1 12.8 + 5.8 1.3 + 0.7  £ 0.27 0.73 0.43 0.96 0.95 0.48 0.83 0.96 0.94 0.83 0.49 0.50 0.51  19  Figure 4. A H R ,  and A H R p PRE-IH and POST-IH. Filled bars = PRE-IH; open bars = POST-IH; A H R y ventilatory response to acute hypoxia; A H R c A V m mean middle cerebral arterial blood flow velocity response to acute hypoxia; A H R M A P mean arterial blood pressure response to acute hypoxia. V E  AHRMCAVIH,  M A  =  =  E  M  =  2 0  - ,  20  In the P R E - I H AHRMCAVIH  there was a strong, positive relationship between the  AHRMAP  and  (r(7)=4.8, p<0.05); although this relationship did not reach statistical significance  during the P O S T - I H AHRMCAVHI  AHR,  and  AHR.  Furthermore, investigation into the difference between  P O S T - I H AHR cAVm M  AHRMAP  and  POST-IH  was strongly associated with a blunted  AHRMCAVIH  Figure 5. Association between the change in A H R M A P and A H R M C A V I U between  P R E - I H and  AHRMAP  showed that a blunted  to the difference between P R E - I H  PRE-IH  AHRMAP  (r(7)=4.4, p<.05) (Figure 5).  POST-IH.  21  Exercise PRE-IH, significant increases in V E occurred in response to the different exercise intensities (F(8,64)=78.2, p<0.05) (Figure 6); V E at 50 W (24.6 ± 7.1 L/min), 100 W (34.0 ± 9.1 L/min), 150 W (48.0 ± 11.7 L/min), Recoveryl (32.9 ± 8.1 L/min), and Recovery2 (23.0 ± 6.1 L/min) were significantly elevated from rest (Table 7). Similarly, V E increased from rest during the POST-IH exercise trial (F(8,64)=127.8, p<0.05). The increases from rest occurred at each exercise intensity, and continued for 2 minutes into recovery. There was no difference in PRE-IH V E and POST-IH V E during the exercise tests (F(8,128)=0.42, p>0.05). During the PRE-IH exercise trial, M C A V m significantly increased from rest at 100 W (72.6 ± 18.0 cm/s) and 150 W (73.5 ± 15.3 cm/s, F(8,64)=8.6, p<0.05) (Figure 6). In contrast, the POST-IH exercise trial only caused a significant increase in M C A V m from rest at 150 W (71.7 ± 11.1 cm/s, F(8,64)=7.6, p<0.05). IH did not result in any change in M C A V m at any exercise intensity (F(8,128)=0.32, p>0.05). M A P during the PRE-IH exercise trial increased from rest at 50 W (106.0 ± 9.4 mmHg), 100 W (111.9 ± 8.0 mmHg), and 150 W (116.5 ± 8.0 mmHg, F(8,56)=36.7, p<0.05). POST-IH, M A P only increased from rest at 100 W (109.4 ± 7.5 mmHg), and 150 W (120.0 ± 10.6 mmHg, F(8,56)=22.9, p<0.05). M A P was not different between the PRE-IH and POST-IH exercise trials (p>0.05) (Figure 6).  22  Figure 6. Ventilation (VE), mean middle cerebral arterial velocity (MCAVm), and mean arterial blood pressure (MAP) in response to exercise and carbon dioxide (5% CO2).  1 6 0 -,  * significantly different from PRE-IH rest t significantly different from POST-IH rest / significantly different from PRE-IH room air condition of same intensity # significantly different from POST-IH room air condition of same intensity  23  Table 7. Ventilatory, and cerebrovascular variables during exercise P R E - I H and  = ventilation; PETCO2 = end tidal partial pressure of carbon dioxide; VO2 = oxygen consumption; M C A V m = mean middle cerebral arterial velocity; M C A V s = systolic middle cerebral arterial velocity; M C A V d = diastolic middle cerebral arterial velocity  rest  pre post  VE (L/min) 10.5 ± 2.7 11.0 + 3.2  50 W  pre post  24.6 22.3  +  pre post  34.0 32.3  +  pre post  48.0 47.1  +  pre post  32.9 32.9  +  pre post  23.0 19.5  +  pre post  15.6 14.4  +  pre post  15.0 13.5  ±  pre post  13.4 12.4  +  100 W  150 W  Recoveryl  Recovery2  Recovery3  Recovery4  RecoveryS  ±  +  +  ±  ±  +  ±  ±  PETC0 (mmHg) 42.3 ± 2.1 40.8 + 2.7  7.1 * 4.9 *  42.7 42.3  +  9.1 * 6.1  43.6 42.8  +  11.7* 9.2  42.9 41.8  +  8.1 * 6.0*  44.1 42.4  +  6.1 * 2.8*  38.2 37.9  +  3.0 * 3.1  38.2 37.8  +  4.5 2.3  38.6 38.9  +  3.5 1.8  39.5 39.3  +  {  {  * significantly different from P R E - I H rest significantly different from P O S T - I H rest  1  to 4^  MCAVm (cm/s) 63.3 + 11.1 61.3 + 9.9  MCAVs (cm/s) 105.8 + 14.7 101.9 + 13.7  3.6* 3.7  70.9 68.6  +  17.4 13.1  125.5 120.7  +  4.2* 7.3  72.6 69.0  +  17.7* 14.2  132.9 125.4  +  8.7* 9.8  73.5 71.7  +  15.3* 11.1 '  135.2 133.3  +  5.1 4.5  68.5 64.0  +  20.3 12.8  129.2 124.4  +  2.5* 3.2*  58.4 56.4  +  12.5 9.0  109.6 107.7  +  3.2 * 2.3*  59.3 57.7  +  11.9 7.9  105.1 103.4  +  1.8* 2.5  62.5 63.1  +  14.0 13.9  105.8 106.6  +  1.7* 2.1  63.3 62.7  +  13.3 10.7  105.3 103.9  +  2  +  ±  ±  +  +  +  +  +  V0 (ml/kg/min) 5.2 ± 2.0 4.2 + 1.0  POST-IH. V E  2  2.5 1.9  15.4 14.5  +  1.7 2.7  19.2 20.3  +  1.9 2.5  29.4 28.1  +  +  +  ±  1  !  !  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  MCAVd (cm/s) 40.2 ± 7.9 39.0 + 7.4  23.3* 19.1  40.9 39.7  +  28.4* 20.1  40.2 39.3  +  26.3* 20.1 *  38.7 37.4  ±  34.8* 24.6*  39.4 35.6  +  24.6 19.4  33.9 32.7  +  22.0 17.4  36.6 35.6  +  22.3 24.7  40.2 40.6  +  20.5 19.9  41.4 40.8  +  t  {  +  +  +  +  +  +  +  +  11.9 8.9 9.8 9.8 8.1 7.0 13.4 8.6 7.0 5.6 * 6.4 4.9 10.3 8.6 9.6 6.7  Table 8. Cardiovascular variables during exercise PRE-IH and POST-IH. M A P = mean arterial pressure; SBP = systolic blood pressure; D B P  rest  50 W  100 W  150 W  Recovery 1  Recovery2  Recovery3  Recovery4  Recovery5  pre post  SBP (mmHg) 133.5 + 7.6 133.7 + 10.9  MAP (mmHg) 96.6 + 5.6 95.7 + 6.3  pre post  106.0 101.6  +  pre post  111.9 109.3  +  pre post  116.5 119.7  +  pre post  98.1 96.7  ±  pre post  98.0 94.1  +  pre post  98.9 94.5  ±  pre post  96.6 94.9  +  pre post  96.8 95.1  ±  +  +  ±  +  +  ±  ±  +  9.4 * 9.2  151.0 146.6  ±  8.0 * 7.5  160.5 159.1  +  8.0 * 10.6 '  173.6 180.8  +  5.3 7.1  137.9 138.5  +  7.2 8.3  134.5 132.3  +  8.1 6.4  134.3 130.6  +  9.3 7.8  129.7 130.7  +  6.6 8.7  129.8 130.2  +  {  * significantly different from PRE-IH rest ' significantly different from POST-IH rest to  +  +  +  ±  +  +  +  ±  104.2 108.9  +  14.4 * 13.5  82.9 78.3  +  119.5 125.6  ±  10.0 * 8.5 '  86.8 83.4  +  8.0 * 6.6  122.9 132.0  +  5.3 * 10.1 '  87.6 88.4  +  9.5 * 8.6*  131.2 136.5  +  4.5 12.0  77.6 75.0  +  6.7 6.0  113.3 118.4  +  6.9 12.2  78.1 73.8  +  7.9 7.5  106.8 111.5  +  9.1 10.4  79.6 75.1  ±  7.9 5.3  102.4 106.7  +  10.3 12.3  78.2 75.4  +  9.4 7.1  99.6 105.8  +  5.7 13.2  78.4 75.8  +  7.2 7.8  99.0 103.5  +  +  +  +  +  +  +  ±  +  HR (bpm)  SV (ml)  DBP (mmHg) 77.4 ± 6.5 75.8 + 6.2 8.2 7.7  f  ±  +  +  +  +  +  +  ±  +  25.2 27.4  60.9 56.9  +  29.8 30.1 *  91.6 86.4  +  28.9 * 32.4  110.9 107.4  +  23.6 * 29.5  129.9 132.1  +  17.4 21.1  102.3 106.8  +  17.3 21.7  89.6 91.4  +  17.8 24.0  84.1 87.7  +  17.1 22.6  79.4 84.4  +  16.7 23.0  80.1 83.2  +  s  1  +  +  +  +  +  +  +  +  +  Q (L/min) 6.3 + 1.9 6.2 + 1.7  10.5 6.5 10.9 * 7.3  10.9 10.8  +  13.5 * 10.0  13.5 14.0  +  14.8 * 15.4  16.9 17.7  23.3 * 24.7  11.4 12.3  +  20.6 * 23.8*  9.4 9.8  +  18.3 * 22.1 '  8.4 9.0  +  19.1 * 19.6'  7.7 8.6  +  17.3 * 19.5'  7.8 8.3  +  4  f  {  s  +  2.9 * 2.5 !  +  3.1 * 3.1  +  2.7 * 2.7  ±  +  ±  +  +  E  2.2 * 2.0 f  1.7 * 1.5 f  1.5 * 1.4* 1.6 1.1  f  1.4 1.2'  CO2 Reactivity Increases in exercise intensity brought about significant increases in V E C O 2 PRE-IH (F(3,24)=143.83, p<0.05); V E at each exercise intensity was different from rest, as well as to one another (p<0.05). Furthermore, hypercapnia resulted in a significant increase in V E when compared to V E at the same exercise intensity while breathing room air (p<0.05) (Figure 6). Similarly, hypercapnia resulted in an increase in V E POST-IH at each exercise intensity (F(3,24)=95.76, p<0.05) which was significantly increased from V E  C  O  2  POST-IH at rest  (p<0.05) (Table 10). Hypercapnia caused a significant increase in V E from room air (p<0.05) breathing at all exercise intensities during the POST-IH exercise trial. There was no significant difference in V E C O 2  a t  a n  Y exercise intensity between PRE-IH and POST-IH trials.  In the hypercapnic condition, increases in exercise intensity were accompanied by significant increases in M C A V m (PRE-IH: F(3,24)=70.6, p<0.05; POST-IH: F(3,24)=47.2, p<0.05). In both the PRE-IH and POST-IH exercise trials, hypercapnia resulted in an increase in M C A V m at each exercise intensity (p<0.05) (Table 9). No significant differences were detected in M C A V m c o 2  a t  a n  Y exercise intensity between PRE-IH and POST-IH.  A significant increase in M A P c o 2  f  r o m  r e s  t occurred during the PRE-IH and POST-IH at  every exercise intensity (PRE-IH: F(3,21)=30.2, p<0.05; POST-IH: F(3,21)=19.7, p<0.05). There was no significant effect of IH on M A P C O 2 trials) (F(3,42)=.41, p>0.05). Also,  MAPCO2  o n  (between PRE-IH and POST-IH exercise  l y increased from room air breathing during the  POST-IH at 100 W (F(3,21)=7.2, p<0.05). M A P o failed to show any significantly increase C  2  from M A P during room air breathing at any other exercise intensities. Although the addition of CO2 caused a significant increase in other cardiovascular variables, there was no difference between the PRE-IH and POST-IH CO2 reactivity trials (Table 9). 26  Table 9. Ventilatory, cardiovascular, and cerebrovascular variables during hypercapnic (5% carbon dioxide) rest and exercise. PETCO2 = end tidal partial pressure of carbon dioxide; M C A V m = mean middle cerebral arterial velocity; M C A V s = systolic middle cerebral arterial velocity; M A P = mean arterial blood pressure; SBP = systolic blood pressure; DBP = diastolic blood pressure; SV = stroke volume; HR = heart rate; Q = cardiac output rest C 0  50 C 0  2  100 C 0  150 C 0  2  2  rest C 0  50 C 0  2  2  2  100 C 0  150 C 0  2  2  pre post  Ventilation (L/min) 16.3 + 5 - 1 / 16.1 ± 3.3 #  pre post  39.8 39.8  +  pre post  57.2 58.2  +  pre post  pre post  P E T C Q (mmHg) 48.1 + 2 . 0 , / 46.7 ± 2.1 # 2  11.5*,/ 8.0 t, #  52.2 50.8  +  14.4 *, / 10.3 t, #  54.8 53.2  +  +  79.5- + 83.0 +  18.8*, / 19.7 t, #  +  MAP (mmHg) 98.9 + 6.8 96.8 + 6.2  pre post  110.8 107.3  +  pre post  117.4 117.3  +  pre post  121.4 120.3  ±  + + +  2,5*,/ 2.4 t, #  87.1 83.1  ±  1.9*,/ 2.5 t, #  99.3 97.0  +  +  56.2 . + 53.7 +  2.7*,/ 3.6 t, #  108.8 106.5  +  +  MCAVs (cm/s) 119.9 + 16.2,/ 113.2 + 15.0 #  MCAVm (cm/s) 74.6 + 13.1/ 71.5 ± 10.3 #  +  ±  +  16.7*,/ 12.3 t, #  146.2 138.9  +  20.5*,/ 18.2 t, #  163.7 159.0  +  22.0*,/ 20.9 t, #  171.5 170.1  +  +  +  +  MCAVd (cm/s) 50.0 ± 9.4,/ 49.4 + 7.9 #  23.9 *, / 18.2 t, #  54.4 51.9  +  28.5*,/ 24.8 t, #  62.9 61.2  +  28.0 *, / 26.7 t, #  70.1 67.0  +  SBP (mmHg) 137.0 + 8.9 133.8 + 8.8  DBP (mmHg) 79.1 + 7.1 77.2 ± 6.3  SV(m I) 106.0 + 25.9 105.4 ± 25.2  HR (bpm) 62.4 + 10.6 62.0 + 8.7  10.3* 7.9 t  156.8 153.5  +  16.8 * 11.1 t  86.4 82.6  +  8.6* 6.9  117.3 125.1  +  31.1 * 28.9 t  93.2 90.9  +  8.1 * 8.8 t, #  167.8 171.2  +  10.2 * 9.2 t, #  90.6 88.5  +  8.2* 7.4 t  123.0 131.5  +  31.0 * 35.5 t  114.3 112.5  +  9.1 * 15.5 t  178.3 180.6  +  9.4 * 14.5 t  90.6 88.0  +  9.7* 11.5 t  131.7 138.1  +  25.1 * 30.9 t  133.8 136.5  +  +  +  +  +  +  +  * significantly different from PRE-IH CO2 rest t significantly different from POST-IH CO2 rest / significantly different from PRE-IH room air breathing of same intensity # significantly different from POST-IH room air breathing of same intensity  +  +  +  +  +  +  +  +  +  12.2,/ 8.2 # 15.2 * , / 13.6 t, # 15.8 *, / 16.8 t, #  Q (L/min) 6.6 + 2.0 6.4 + 1.5  11.6 * 5.1 t  10.8 11.3  12.9 * 10.2 t  13.9 14.6  14.4 * 16.5 t  17.4 18.6  + + + + + +  3.0* 2.5 t 3.1 * 3.4 t 2.6 * 2.9 t  .  DISCUSSION Main Findings The purpose of this study was to investigate the effects of IH on ventilatory, cardiovascular, and cerebrovascular regulation during acute hypoxia at rest, and during submaximal exercise. This study reports several main findings: 1) the results are in agreement with several lines of evidence that show IH to cause no change in baseline ventilatory, cardiovascular, and cerebrovascular variables; 2) the effect of IH on cerebrovascular regulation during acute hypoxia was blunted in certain subjects; 3) there was an association between the changes in cardiovascular and cerebrovascular regulation following IH; 4) IH did not change ventilatory, cardiovascular, or cerebrovascular regulation during submaximal exercise; 5) ventilatory, cardiovascular, and cerebrovascular regulation was maintained during hypercapnia following IH both at rest and submaximal exercise.  Effect of IH on Ventilatory Regulation Arterial partial pressure of oxygen is continuously monitored by peripheral chemoreceptors (carotid bodies). Accordingly, the carotid body has been implicated as playing a key role in the ventilatory changes following IH (111). In the rat model, Peng et al. (111) investigated carotid body sensory activity to repeated bouts of hypoxia (12% O2). They found a reversible increase in baseline (normoxia) sensory activity as the repeated bouts of hypoxia progressed; this phenomenon is known as long-term facilitation (LTF) (111). In contrast, rats that were exposed to sustained hypoxia did not exhibit LTF. The same group also found IH to cause an increased carotid body sensitivity to acute hypoxia of the same intensity (112), which is termed progressive augmentation (123). Similarly, this increase in sensitivity was transient, where increases in carotid body sensitivity following IH (15 s of 5% O2 at 5 min intervals, 9 bouts/hour, 8 h/day, 10 days) is eliminated following 10 days of normoxia (112). It is important 28  to mention that the patterning and severity of hypoxia was a central component to the change in carotid body sensitivity. Although there was a trend for a change in the  following IH (PRE-IH: 5.9 ± 2.3  AHRVE  L/min; POST-IH: 7.6 ± 4.4 L/min), the change did not reach statistical significance. Many lines of evidence have shown IH to cause an increase in the A H R y (5, 33, 75, 77, 78, 95). Katayama E  et al. (75) measured the A H R  V E  in six subjects following seven days of simulated altitude (4,500  m, lhr/day). IH caused an increase in the A H R y which was maintained one week following IH E  (75). Also, our lab has shown different protocols of IH (e.g. short duration IH and long duration IH) in a lab setting to cause significant increases in the A H R y (33, 95). Foster et al. (33) found a E  significant increase in the A H R y following 10 days of two different IH protocols (short E  duration: 5 min 12% O2 at 5 min intervals for one hour; long duration: 30 min 12% O2). Although the IH protocols were not identical to the current study, an increase in the A H R y was E  expected nonetheless. The ventilatory response to acute hypoxia has been reported to be quite variable (29, 52, 147, 152), which could help explain the discrepancy in our results. Given this, other studies have failed to show an increase in the  AHRVE  following hypoxia exposure (35, 76,  98). Even though Foster and colleagues (33) showed a significant increase in the A H R y  E  following IH, not all subjects reached their greatest increase immediately following IH. Rather, the  AHRVE  in certain subjects reached their peak before, as well several days following IH. It is  possible that the design of the current study did not allow for detection of each subject's greatest increase in A H R y . Thus, it is conceivable that the time course of progressive augmentation is E  individualistic, and testing the A H R y at a single time point following IH could miss this effect. E  Most analogous to the current study, Lusina et al. (95) found a 49% increase in the A H R following 10 days of isocapnic IH. However, differences in the  AHRVE  V E  protocols could partially  explain the conflicting results between the current study and that of Lusina et al. (95)  29  Although the data does not display a clear increase in A H R y , we do consider it probable E  that our protocol was severe enough to have caused changes in chemosensitivity. To support this statement, it is important to consider ventilation during the IH sessions. Figure 2 shows an increase in V E (from rest) over the 10 days of IH. This shows a significant increase (0.29 L/min • day" ) in V E as the IH protocol progressed. Therefore, this data alone demonstrates progressive 1  augmentation. Anecdotally, many of the subjects noted that they did not notice the hypoxia during the IH sessions, whereas they found breathing during the A H R y somewhat difficult due E  to the 'thin air'. Perhaps this could imply that behavioural factors masked any progressive augmentation that did occur. If we consider that the behavioural aspect of hypoxic ventilation was eliminated or minimized during the IH, then the current study would support research that has shown IH to cause an increase in the AHRy . Although LTF was discussed in the animal E  model, the existence of LTF in the human model is much less observed (123). Our data clearly shows no LTF effect, and is consistent with many other human studies (33, 68, 100). It has been suggested that IH is an effective way to preaclimatize before high-altitude climbing, for example IH has been suggested to improve mitochondrial respiration (136). Katayama et al. (72) found 3 weeks of IH (4,500 m simulated altitude for 90 min, 3 days/week) to cause a decrease in oxygen consumption during submaximal exercise, although there was no change in V E during submaximal exercise following IH. The same group supported these findings with the use of a more intense IH protocol (-12% O2, 3 hrs/day, 14 days) (73), suggesting IH to produce an increased submaximal exercise efficiency (72). Our data show no change in submaximal V E or VO2 following IH (Table 7). Explanation for the lack of consistency between our results and the results of others, may be due to the severity of hypoxia experienced. Studies from Katayama et al. (72, 73) which showed a reduced VO2 following IH implemented an IH (1.5-3 hr/day, 14-21 days) which was much more severe then that of the current study (1 hr/day, 10 days). Further, the same group has also shown no change in 30  submaximal VE and VO2 during submaximal exercise following IH (4,500 m simulated altitude, 1 hr/day, 7 days) (77). This is consistent with our data. Therefore, it is difficult to draw any definitive conclusions about ventilatory parameters during submaximal normoxic exercise following IH. Although we found a trend for an increase in the A H R , there was no change in VE  VECO2  following IH at rest or during submaximal exercise (Table 9). This is consistent with many other studies (33, 74, 76). Foster et al (33) found no change in the ventilatory response to CO2 following two different protocols of I H (short duration: 5 min 12% O 2 at 5 min intervals for one hour; long duration: 30 min \2% O 2 ) . Similarly, Katayama and colleagues found no change in the ventilatory response to CO2 following IH with the use of a hypobaric chamber (4,500 m simulated altitude) (74, 76). In contrast, Ainslie et al. (6) demonstrated an increase (48%>) in the VECO2  following five nights of simulated altitude (hypoxic tent; F i 0 ~ 13.8%), which then 2  normalized to baseline five days following the last night of hypoxia. The authors of that study suggest that their atypical results are due to the severity of IH. To substantiate this claim, Schoene et al. (133) had subjects simulate a 40 day ascent of Mt. Everest (hypobaric chamber). A n increase in the  VECO2  w  a  s  found at 305 Torr, but not at 428 Torr. Also, the majority of  studies that have shown no change in the  VECO2  have utilized an isocapnic IH protocol. It has  been suggested that IH will only cause in increase in the  VECO2  under poikilocapnic hypoxia;  thereby producing respiratory alkalosis (6). Collectively, it appears that the current study did not show a change in the  VECO2  d  u e t 0  m  e  severity o f the IH protocol and the use of a n isocapnic IH  protocol.  31  Effect of IH on Cardiovascular Regulation The increase in M A P in response to hypoxia is a multifaceted response, which includes influences from increases in H R and possibly sympathetic influences (129). There is also strong evidence for the influence from activation of arterial chemoreceptors (47, 94). Similar to the AHRVE,  an increase in the  AHRMAP  has been shown to occur following extended hypoxia  exposure, although no change occurs in the  AHRHR.  Insalaco et al. (63) found the  AHRMAP  to be  increased following one day at altitude (5,050 m), which was elevated further following 24 days at altitude. Also, many investigators have shown an increase in the  AHRMAP  following IH.  Katayama et al. (78) detected an increase in both the systolic and diastolic blood pressure response to acute hypoxia following seven days of IH (4,500 m simulated altitude, 1 hr/day), while no change was detected in the H R response to acute hypoxia. In addition, our lab has shown a trend for an increase in the systolic and diastolic blood pressure responses to acute hypoxia following IH (33). In contrast, a study by Lusina et al. (95) found no change in the blood pressure response to acute hypoxia following isocapnic IH (Sa02 = 80%, 1 hr/day, 10 days). As of yet, our lab has failed to show a change in the  AHRHR  following IH, which is consistent with  other findings (63, 78). Although this is not the first study to show no change in the  AHRHR  following IH, the reasoning for this is still uncertain. It has been suggested that the regulation could be the result of the coordination of multiple systems, which include carotid and aortic chemoreceptor reflexes, lung inflation receptors, and baroreflexes (78). Clearly, more research is needed to elucidate this issue. In addition, there was no effect of IH on the AHRsv and  AHRQ.  The AHRsv and A H R Q appear to be quite variable, and the effect of IH on the AHRsv and  AHRQ  has not been highly documented. Similar to the Lusina et al. (95) study, the current study did not show any effect of IH on the  AHRMAP, AHRSBP, AHRDBP,  or A H R H R . There are multiple  explanations for the lack of increase in blood pressure response to acute hypoxia. First, the protocol used to test the blood pressure responses to acute hypoxia may have not been sensitive 32  enough to detect blood pressure changes. In fact, the acute hypoxic test did not cause a significant increase in M A P , SBP, or DBP. Similarly, Imadojemu et al. (59) found no increase in M A P during five minutes of 10% O2, an Fi02 similar to that achieved in the current study (~11%> O2). Comparable results were observed by Van M i l et al. (146) where 20 minutes of hypoxia (Sa02 = 80%i) caused no change to M A P . Second, the IH protocol employed in the current study may not have been severe enough to cause an increase in carotid body sensitivity, thereby increasing blood pressure sensitivity. To support this, Fletcher et al. (30) found IH to cause an increase in resting rat blood pressure; however, the increase was abolished in rats which had undergone carotid body denervation, implying a requisite role of the carotid body for changes in M A P . Although the current study shows a trend for an increase in the A H R v , it did not reach E  significance. Therefore, it appears that the IH protocol used in this study was not severe enough to cause the increase in carotid body sensitivity explaining the lack of increase in the AHRSBP, AHRDBP,  AHRMAP,  and A H R V E - Lastly, it is possible that a short duration-type of IH protocol is  required to evoke an increase in the  AHRMAP-  In the rat model, carotid body sensitivity has been  shown to increase after a short duration IH protocol (15 s o f 5 % 0 2 + 5 min of 21% O2, 9 episodes/h, 8 h/day, 10 days), and not following a long duration IH protocol (4 h of hypobaric hypoxia (0.4 atm/day) + 20 h of normoxia, 10 days) (112). During rhythmic muscular activity, measurable increases in M A P occur; due to an increase in SBP. Wang et al. (148) measured the M A P response to a graded exercise test (bicycle) before and after either 'moderate' (15% O2) or 'severe' (12% O2) IH (1 hr/day, 5 days/week, 4 weeks). A greater increase in M A P was shown to occur in the group who underwent the severe IH protocol. In contrast, the current study did not show any change in the blood pressure response to submaximal exercise following IH; although the exercise intensity was demanding enough to cause an increase in blood pressure. Rationale for the difference between the current study and that by Wang et al. (148) is twofold. First, the IH protocol used by 33  Wang et al. (148) (4 weeks) was much longer then that of the current study (10 days). They found a blunted hyperaemic response on the subjects in the severe IH group, but not in the moderate IH group. The authors suggested this was due to an impaired NO response, since there was a blunted reactive hyperaemia response and dilation to acetyclcholine; however, neither of the groups demonstrated a change in the dilatory response to sodium nitroprusside. It is possible that their study was severe enough to attenuate the shear-stress induced vasodilation during exercise, due to decreased bioavailability of NO (148). Second, in the severe IH group, the increase in the M A P response to exercise occurred at an exercise intensity of/or greater than 160 W. The highest exercise intensity that we used was 150 W. It is possible that our protocol was not intense enough to show any effect of IH on blood pressure during exercise. In general, our data show no increase in any cardiovascular variable in response to hypercapnia. The implementation of a hypercapnic gas was to test cerebrovascular regulation, rather than cardiovascular regulation. Our data is consistent with previous literature. Serebrovskaya (135) found no change in the blood pressure response to a rebreathing hypercapnic protocol. In fact, a slight decrease in SV was observed, and a small increase in Q was observed once PETCO2 reached high values (-58 mmHg). The increase in Q was attributed to an increase in HR. Our data shows an increase in M A P (due to an increase in SBP) at one time point (POST-IH, 100 W) in response to hypercapnia. The highest PETCO2 experienced by our subjects was under hypercapnic conditions at 150 W, where they reached -56 mmHg. This was accomplished with the administration of 5% CO2. Even though CO2 can cause an increase in cardiovascular variables (e.g. SBP, DBP, M A P , HR), it is most often the result of intense hypercapnia (>7% CO2) (134). It is possible that the intensity of CO2 was not great enough to cause changes in cardiovascular variables.  34  Effect of IH on Cerebrovascular Regulation Hypoxia, a potent vasodilator, initiates an increase in CBF (12). The response is multifaceted, which includes NO, adenosine, K , and prostaglandins (48, 128, 146). Van M i l et +  al. (146) measured the change in CBF during hypoxia with and without infusion of L - N M M A . In the normoxic condition, no change was observed in CBF following infusion of L - N M M A , whereas in the hypoxic condition CBF significantly increased, after which it decreased following L - N M M A infusion. The authors suggested NO to be a key regulator of cerebral vessel dilation to hypoxia (146). In contrast, IH has been shown to alter the typical response of NO to hypoxia. Phillips et al. (113) found a decrease in the vasodilatory response of cerebral (middle cerebral) and peripheral (gracilis) arteries to acute hypoxia, which was attributed to an IH-induced decreased bioavailability of NO. Similar results are found in a human disease model, where sleep apnea sufferers have a reduced CBF response to acute hypoxia; however the response is normalized following four to six weeks of continuous positive airway pressure (CPAP) therapy (32). Lastly, in a healthy human model, our lab has shown 10 days of IH to cause cerebral dysregulation to acute hypoxia, measured both via near-infrared spectroscopy (33) and transcranial Doppler (unpublished). Lavie et al. (91) found sleep apnea patients to have significantly lowered levels of circulating NO in comparison to healthy controls. Further, nine months of CPAP therapy significantly increased circulating NO and L-arginine (91). IH (hypoxia/reoxygenation) can produce ROS and an inflammatory response (22), which leads to oxidative stress (90). Similar to the animal model, in the human disease model (sleep apnea), the development of ROS and oxidative stress causes dysregulation of NO which results in a blunted forearm vessel dilation to acetylcholine but not to sodium nitroprusside (exogenous N O donor) (79).  This suggests that sleep apnea patients have a normal smooth muscle response, although an  impaired endothelium-dependent dilation. Given this, we expected our subjects to have a blunted CBF response to acute hypoxia following IH; however, this was not necessarily the case. As a 35  group, the POST-IH  AHRMCAVHI  (3.7 ± 3 . 7 cm/s) was almost identical to the PRE-IH  (3.9 ± 9.2 cm/s). Individually, five subjects displayed a blunted  AHRMCAVIH  AHRMCAVIII  following IH,  whereas four subjects showed an increase (Figure 4). The variability in the change in A H R M C A V I H warrants discussion. The rationale for maintaining the IH sessions at 80% was to expose each individual to the same absolute hypoxic stimulus. If we were to set the IH sessions at a desired Fi02, which is most often used in this type of study design, the hypoxic stimulus would differ between individuals. Since the ventilatory response to hypoxia is variable between individuals, standardizing the Fi02 would most likely result in a different Sa02 between individuals. However, we still observed variability in the  AHR cAv M  m  in response to IH, In fact, this is  consistent to what we have previously shown in our lab. Foster et al. (33) found a blunted cerebral oxygenation sensitivity (NIRS) following 10 days of isocapnic IH. However, it is important to note that two different protocols of IH were employed in this study; a short duration (5 min 12% O2 at 5 minute intervals, 1 hr/day, 10 days) and a long duration protocol (30 min 12%i O2, 10 days). The blunted cerebral oxygenation response was primarily driven by the short duration group; specifically, eight of the nine subjects in the short duration group showed a blunted response whereas only five of the nine in the long duration group showed the blunted response. The protocol in the current study is most similar to the long duration group in the Foster et al. (33) study. Similar to these results, we also found that five of the nine subjects in the current study to show a blunted have played a key role in the  AHRMCAVITT  AHRMcAVm-  As discussed earlier, the patterning of the IH may  In a preliminary study, we found the  AHRMCAVITI  to be  blunted following a short duration IH protocol which mimicked the short duration protocol in the Foster et al. (33) study. Also, if we consider animal work, it is possible that our protocol did not continue long enough to cause consistent vessel dysregulation. Phillips et al. (113) found a blunted vessel dilatory response to acute hypoxia in rat cerebral arteries following 14 days of IH (Fi02 = 10%o for 1 min at 4-min intervals, 12 h/day). Similar lines of evidence in the animal (30, 36  31) and human (148) models required -28-35 days of IH to show vascular dysfunction. Therefore, although ROS production can increase quickly in response to hypoxia (141), the length of time needed for ROS to cause a measurable effect on the bioavailability of N O may be longer. In contrast, Kolb et al. (84) found an increase in the CBF response to acute hypoxia following five poikilocapnic hypoxic nights (Fi02 ~ 13.8%, 8 hrs/day). Additionally, Jensen et al. (66) showed an enhanced CBF response to acute isocapnic hypoxia following 5 days of altitude acclimatization (3,810 m). However, since the hypoxia exposure was at altitude, CO2 was not controlled. Also, these two studies resemble more of a long duration hypoxia exposure which results in different ventilatory, cardiovascular and cerebrovascular adjustments to short duration exposures. More recently, Ainslie et al. (2) found an increase in the CBF response to acute poikilocapnic hypoxia following 10-12 days of IH (5 minutes at a Sa02 of 78-88% at five minute intervals, 90 mins/day). Methodological considerations for this study reveal problems for comparison to the current study. First, their sample included both males and females. Progesterone and estrogen vary across the menstrual cycle (~2-8 mmHg) which has direct ventilatory and cerebrovascular consequences (43, 86). Considering the length of their protocol, female sex hormones would have likely affected the results. Most importantly, the protocol to measure the response to hypoxia was poikilocapnic. The CBF response to acute hypoxia when CO2 is not controlled is quite variable. In fact, the change in CBF to poikilocapnic hypoxia (4,559m simulated altitude) in one study has been shown to range from a 3%> decrease to a 20%> increase, and the variability increases with time in hypoxia (10). Comparison of the current study's results to that of Ainslie et al. (2) is problematic due to these reasons. Although most research has attributed alterations in CBF following IH to changes in the cerebral vessels' ability to vasodilate, it is important to also consider perfusion pressure. Our 37  results showed an association (r = 0.86) between changes in A H R M C A V I H and those individuals who showed a blunted show a blunted  AHRMCAVHV  AHRMAP  AHRMAP;  therefore,  POST-IH compared to PRE-IH were likely to  This points to a key role of perfusion pressure in CBF changes.  Ainslie et al. (2) found an increase in both the M A P and CBF response to acute hypoxia following IH. Collectively, this could suggest that the changes observed in the CBF sensitivity were at least partially mediated by the changes in M A P sensitivity. Typically, cerebral autoregulation is effective in maintaining CBF constant to changes in arterial pressure. This system responds quickly, where changes in CBF in response to changes in M A P usually last only a few seconds (1). However, cerebral autoregulation appears to be impaired in hypoxia and highaltitude residents (65). Iwasaki et al. (64) found cerebral autoregulation to be impaired at an Fi02 of 15%, but not at \7% or 19%. Similarly, Ainslie et al. (7) found the CBF and M A P sensitivities to acute hypoxia were related during hypercapnic and isocapnic hypoxia, but not during poikilocapnic hypoxia. In contrast, Ainslie et al. (3) recently reported cerebral autoregulation to be maintained during acute hypoxia (Fi02 = 12%>, 20 minutes). Also, administration of hyperoxia can improve autoregulation in high-altitude dwellers (65). It is apparent that evidence regarding the effect of hypoxia on cerebral autoregulation is far from conclusive, and more work is needed. Exercise increases flow to vascular beds, which includes the brain (19, 45, 56, 60, 71, 93, 105, 107, 115-117). It is thought that the increase in flow in vessels of working muscles and the brain results in an increase in shear stress, thereby releasing NO from the endothelium (38, 102). In the animal model, the increase in flow has shown vasodilation (in situ), which is abolished by removal of the endothelium (140). In the current study, M C A V m significantly increased from rest at 150 W in both the PRE-IH and POST-IH exercise trials; there was no effect of IH on CBF during submaximal exercise. This is somewhat expected since there was no change in the AHRMCAVIH-  However, the subjects that showed a decrease in the  AHRMCAVITI  following IH, did  not necessarily show a change in M C A V m during exercise. We would expect that subjects who 38  had a blunted  AHRMCAVIH  following IH would have a decreased bioavailability of NO, thus  decreasing the M C A V m during exercise. Even though NO has been implicated as a major cause for vessel dilation from increased shear stress (23), the increase in flow during exercise can be due to other reasons, including the release of metabolites, myogenic properties of the vessels, increase in metabolism, autonomic neural control, and mechanical factors (99). There is a possibility that other mechanisms made up for the vasodilation during exercise that was originally caused by the release of NO, or the contribution of NO to exercise-induced vasodilation is not as important as thought by some (23, 38). Even though the study design does not provide information regarding the mechanism of CBF regulation during exercise, it appears that cerebrovascular regulation is maintained during submaximal cycle exercise following I H . In the rat model, N O has been shown to significantly contribute to cerebral vessel dilation during hypercapnia (55). Similarly, patients with endothelial dysfunction (e.g. diabetes mellitus and/or hypertension) show a reduced cerebral CO2 reactivity, which is improved with infusion of L-arginine or sodium nitroprusside (89, 153). Therefore, we would expect our subjects to have a decreased CO2 reactivity following IH. However, there was no difference in M C A V m c o 2 between PRE-IH and POST-IH at rest or during exercise. Also, there was no association between the changes in A H R M C A V I T I and M C A V m c o - As discussed earlier, there is a possibility that our 2  protocol was not severe enough to cause a change in the bioavailability of NO. Also, the regulation of CBF in hypercapnia is not entirely dependent upon NO. It has been found that C 0  2  and pH have a direct effect on vessel tone; although the mechanisms of action are unclear (12, 48, 87). Therefore, even i f our IH protocol was severe enough to cause a decreased bioavailability of NO, there is the possibility that.the M C A V m c o 2 would remain unchanged. We also designed the current study on the assumption that IH would cause endothelial dysfunction, thereby impairing endothelial-derived NO. It is important to note that N O is not produced solely by the endothelium. In fact, Toda et al. (145) found the cerebral vessel (dog basilar and middle 39  cerebral arteries) response to hypercapnia was unchanged after endothelial denudation. However, application of the findings to the current study is problematic since the study by Toda et al. (145) used much higher levels of CO2 (5-15%). In contrast to the current study and previous literature, Kolb et al. (84) found IH (~13.8%> O2, 8 hr/day, 5 nights) to increase the CBF response to acute hypercapnia. Unfortunately, this is the only study to report this finding and, to our knowledge, physiological rationale for this change has not been documented.  Summary of Results in Context of Hypotheses This study was designed in order to specifically test three hypotheses. It was hypothesized that in comparison to baseline, IH would result in:  (1) An increased V E , and MAP response to acute hypoxia, and a blunted CBF response to acute hypoxia. The results of this study show high variability in the change in the V E response to acute hypoxia following IH. As a result, there was no significant increase in V E chemosensitivity following IH, which does not support our hypothesis. Measuring V E chemosensitivity simply once following IH may be insensitive to changes due to large intra- and inter-individual variability. Nonetheless, we are confident the IH protocol did alter V E chemosensitivity, as supported by the progressive increase in V E in response to hypoxia throughout the 10 days of IH. The data also did not support our hypothesis for an increased M A P response to acute hypoxia following IH. Research has suggested a key role of the carotid body for an increase in M A P during hypoxia (94). Although our study did not directly measure carotid body sensitivity, the non-significant change in M A P chemosensitivity suggests that the IH was not severe enough or did not contain adequate hypoxia iterations to cause an increase in carotid body sensitivity. This was supported by no change in V E chemosensitivity measured on PRE-IH and POST-IH tests. 40  There is evidence to show IH to increase ROS which decreases the bioavailability of NO, thereby reducing cerebral vessel dilation to hypoxia (113). However, contrary to our hypothesis, IH did not alter cerebrovascular chemosensitivity. Although we have reason to believe the IH did increase ROS (141), the physiological relevance is unclear; other compensatory mechanisms (e.g. adenosine) may have counteracted the maladaptive effect of IH. Despite that, the change in cerebrovascular chemosensitivity was highly related to the change in M A P chemosensitivity, which suggests a key role of perfusion pressure in C B F changes. The change in the V E , M A P and C B F response to hypoxia is highly susceptible to the length, severity, and pattern of the IH protocol, which could have contributed to data which did not support our hypothesis. Although difficult due to logistical reasons, it would be beneficial to measure the V E , M A P and C B F responses to hypoxia throughout a long-term (months to years) IH study in humans to obtain the time-course of the cardiorespiratory and cerebrovascular chemosensitivity changes. (2) A blunted CBF response to submaximal exercise. The data does not support the hypothesis, since IH did not alter C B F during exercise. C B F increased in response to exercise intensity, however, the magnitude of change was similar between the PRE-IH and POST-IH exercise tests. Although some have implicated N O as a key variable for exercise-induced vasodilation (38), it has also been suggested that the contribution of NO is overemphasized (28). If IH did in fact decrease available NO, it is possible that metabolic, neural, and mechanical mechanisms compensated to ensure adequate C B F during exercise.  (3) A reduced CBF response to hypercapnia at rest and exercise. Eliminating the contribution of N O during hypercapnia in a rat model reduces the typical increase in C B F (55). Similar results are found in humans with endothelial dysfunction (89). In the current study, C B F during hypercapnia was similar on PRE-IH and POST-IH tests, which does not support our hypothesis. Although the complete mechanism for hypercapnic vasodilation is unclear, CO2 and 41  pH can have direct effects on cerebral vessel tone (48). Therefore, although we did not directly measure endothelial function, CBF during hypercapnia at rest may have been preserved following IH due to the direct effect of CO2 and pH. In terms of the maintenance of CBF during exercise with the addition of hypercapnia, the regulation of CBF during exercise is a multifaceted system and endothelial dysfunction may play a smaller role during exercise due to other compensatory factors (e.g. cerebral metabolism). The lack of support for our hypotheses prompts serious consideration into the pattern of IH, as well as the mechanisms thought to be responsible for the physiological changes. The length of the protocol appears to dictate whether IH produces beneficial or harmful effects, and it is ill-advised to assume that the point where IH changes between helpful and harmful is the same for all physiological systems. Also, the mechanistic reasoning for the physiological changes needs extensive investigation, since it is a true integrative response. Unfortunately, the design of the current study only allows for speculation as to the mechanisms responsible.  Limitations The study of the physiological responses to hypoxia by non-invasive means requires assumptions to be made about the measurement techniques. In the current study, M C A V was measured via TCD and taken to represent CBF. This measurement technique provides beat-bybeat measurement of changes in the vessel's blood velocity. It is calculated from the maximal frequency of the Doppler shift, which is assumed to represent the mean flow in the centre of the vessel. Interpretation of an increase in C B F V as a reflection of an increase in flow is also dependent upon the assumption of a constant diameter of the insonated vessel. Our protocol included the use of hypoxia and hypercapnia. Although hypoxia and hypercapnia induce increases in flow via vasodilation, it is likely that changes in CBF were not due to changes in diameter of the M C A . With the use of the TCD power (a measure of the amount of red blood 42  cells ) Poulin et al. (121) found no change in the diameter of the M C A during hypoxia, or hypercapnia. These findings have been supported with the use of magnetic resonance imaging (137). TCD is often implemented for investigations into beat-to-beat changes to cerebral perfusion, especially during exercise. It should be noted that changes in flow can also be modified depending on the vessel insonated. Hellstrom et al. (49) measured the changes in the internal carotid artery (ICA), common carotid artery (CCA), and middle cerebral artery (MCA) during increasing workloads. The ICA and M C A both experienced increased blood flow at the onset of exercise, which decreased at the highest workload. In contrast, the C C A increased at every workload; it did not experience the decrease at the higher work rates as the ICA and M C A did. This suggests that conclusions drawn with the use of this technique may be limited (37, 122). Contrary to information suggesting that flow is distributed evenly between major arteries, this study by Hellstrom et al. (49) suggest that flow to the brain is not evenly distributed during exercise. However, the current study utilized the M C A for insonation in order to compare results with other literature. Similar to other methods, TCD requires a high-quality signal which can be compromised by head movement, especially during exercise; although the use of a custom-made headband device can help minimize artifacts produced by small head movements (122). Throughout the acute hypoxic response and I H , we measured arterial oxyhaemoglobin saturation via pulse oximetry. Ideally, measurement of arterial gas concentrations would have been performed. Pulse oximetry does not account for changes in temperature or pH, which can affect oxygen-haemoglobin binding. However, we do not expect the subjects to have experienced drastic changes in temperature or pH, since the testing environment was maintained at room temperature and isocapnia was maintained during the acute hypoxic tests. The A H R V E can be a variable measure (29, 52, 147, 152), therefore the measurement at two time points may not have been ideal; however, similar study designs have previously shown change's in the A H R  V E  (75, 78, 95). Our lab has shown repeated A H R y measurements (five E  43  times) to yield a mean individual coefficient of variation of 27% (83), which is similar to what others have reported (152). In addition, the testing environment was kept tranquil in order to keep the subject calm, thus minimizing behavioural influences on V E . The current study was based on the assumption that IH would increase ROS, decreasing the bioavailability of NO, thereby impairing the vasodilatory response to hypoxia and exercise. Steiner et al. (141) discovered graded hypoxia (15%o 0 , 10% O2, 7.5% 0 ) to cause significant 2  2  increases (123%, 147%, 167% of control, respectively) in DHR fluorescence, a marker of ROS, in rat vessels. During the IH in the current study, Fi02 was ~ 11%; therefore it is probable that our IH protocol did in fact cause an increase in ROS. Unfortunately, we did not directly measure ROS in our subjects, and there is a possibility that an increase in ROS did not necessarily impair NO function; or our measurement techniques were not sensitive enough to detect the effect. A final limitation concerns the recruitment for the study. Subjects consisted of healthy, college-aged males. Therefore, the findings can only be extended to this population. Although much of the study design was based on a clinical model (sleep apnea), comparison is difficult since sleep apnea patients most often have confounding ailments (e.g. obesity). Also, we did not include a control/sham group that underwent 10 consecutive days of breathing room air. Therefore, the possibility of a placebo effect does exist. Due to the logistics of the study design, a sham group is rare in IH studies. Given this, the conclusion of studies which have included a control group are unchanged (72, 77, 78).  Conclusions The results from this study indicate that our IH protocol did not cause any form of ventilatory, cardiovascular, or cerebrovascular long-term facilitation, which is consistent with many other lines of evidence. Contrary to other studies, the current study did not show an increase in the ventilatory or cardiovascular sensitivities to acute hypoxia following IH. Rather, 44  there was a progressive increase in V E during I H over the 10 days, indicating that our study did alter ventilatory chemosensitivity. Our data also suggests that cerebrovascular regulation to acute hypoxia following AHRMCAVIH  I H may  in response to  be individualistic. There was an association between the IH.  AHRMAP  and  This suggests that perfusion pressure at least partially mediates the  changes in A H R M C A V I H following  IH.  To our knowledge, this is the first study to investigate the  effect of I H on CBF during exercise. The results from this study indicate that ventilatory, cardiovascular and cerebrovascular regulation is unchanged during submaximal exercise. Further research is needed to investigate the effect of I H length on the cerebrovascular changes to acute hypoxia and exercise.  45  REFERENCES 1. Aaslid R, Lindegaard KF, Sorteberg W, and Nornes H. Cerebral autoregulation dynamics in humans. Stroke 20: 45-52, 1989. 2. Ainslie PN, Barach A, Cummings KJ, Murrell C, Hamlin M, and Hellemans J. Cardiorespiratory and cerebrovascular responses to acute poikilocapnic hypoxia following intermittent and continuous exposure to hypoxia in humans. JAppl Physiol 102: 1953-1961, 2007. 3. Ainslie PN, Barach A, Murrell C, Hamlin M, Hellemans J, and Ogoh S. Alterations in cerebral autoregulation and cerebral blood flow velocity during acute hypoxia: rest and exercise. Am J Physiol Heart Circ Physiol 292: H976-983, 2007. 4. Ainslie PN, Burgess K, Subedi P, and Burgess KR. Alterations in cerebral dynamics at high altitude following partial acclimatization in humans: wakefulness and sleep. J Appl Physiol 102:658-664,2007. 5. Ainslie PN, Kolb JC, Ide K, and Poulin MJ. Effect of five nights of normobaric hypoxia on cardiovascular responses to acute isocapnic hypoxia in humans: relationship to ventilatory chemosensitivity. Ergonomics 48: 1523-1534, 2005. 6. Ainslie PN, Kolb JC, Ide K, and Poulin MJ. Effects of five nights of normobaric hypoxia on the ventilatory responses to acute hypoxia and hypercapnia. Respir Physiol Neurobiol 138: 193-204, 2003. 7. Ainslie PN and Poulin MJ. Ventilatory, cerebrovascular, and cardiovascular interactions in acute hypoxia: regulation by carbon dioxide. J Appl Physiol 97: 149-159, 2004. 8. Balady GJ, Berra KA, Golding LA, Gordon NF, Mahler DA, Meyers JN, and Sheldahl LM. ACSM's Guidelines for Exercise Testing and Prescription. Maryland: Lippincott Williams & Wilkins, 2000. 9. Bananian S, Lehrman SG, and Maguire GP. Cardiovascular consequences of sleeprelated breathing disorders. Heart Dis 4: 296-305, 2002. 10. Baumgartner RW, Spyridopoulos I, Bartsch P, Maggiorini M, and Oelz O. Acute mountain sickness is not related to cerebral blood flow: a decompression chamber study. J Appl Physiol 86: 1578-1582, 1999. 11. Bergo GW and Tyssebotn I. Cerebral blood flow and systemic hemodynamics during exposure to 2 kPa CO2-300 kPa 0 2 in rats. J Appl Physiol 78: 2100-2108, 1995. 12. Betz E. Cerebral blood flow: its measurement and regulation. Physiol Rev 52: 595-630, 1972. 13. Blitzer ML, Lee SD, and Creager MA. Endothelium-derived nitric oxide mediates hypoxic vasodilation of resistance vessels in humans. Am J Physiol 271: HI 182-1185, 1996.  46  14. Bogert LW, Erol-Yilmaz A, Tukkie R, and Van Lieshout JJ. Varying the heart rate response to dynamic exercise in pacemaker-dependent subjects: effects on cardiac output and cerebral blood velocity. Clin Sci (Lond) 109: 493-501, 2005. 15. Borgstrom L, Johannsson H, and Siesjo BK. The relationship between arterial po2 and cerebral blood flow in hypoxic hypoxia. Acta Physiol Scand 93: 423-432, 1975. 16. Briebach T, Laubenberger J, and Fischer PA. [The effect of physical stress on the blood flow velocity in the middle cerebral artery. A transcranial Doppler sonographic study]. Ultraschall Med 10: 250-253, 1989. 17. Brisswalter J, Arcelin R, Audiffren M, and Delignieres D. Influence of physical exercise on simple reaction time: effect of physical fitness. Percept Mot Skills 85: 1019-1027, 1997. 18. Brooks GA, Fahey TD, and Baldwin KM. Cardiovascular Dynamics During Exercise. In: Exercise Physiology: Human Bioenergetics and Its Applications (4th ed.). New York: McGraw-Hill, 2005, p. 340-362. 19. Brys M, Brown CM, Marthol H, Franta R, and Hilz MJ. Dynamic cerebral autoregulation remains stable during physical challenge in healthy persons. Am J Physiol Heart Circ Physiol 285: H1048-1054, 2003. 20. Carlson JT, Hedner J, Elam M, Ejnell H, Sellgren J, and Wallin BG. Augmented resting sympathetic activity in awake patients with obstructive sleep apnea. Chest 103: 17631768,1993. 21. Clarke C. Acute mountain sickness: medical problems associated with acute and subacute exposure to hypobaric hypoxia. Postgrad Med J82: 748-753, 2006. 22. Conner EM and Grisham MB. Inflammation, free radicals, and antioxidants. Nutrition 12: 274-277, 1996. 23. de Wit C, Schafer C, von Bismarck P, Bolz SS, and Pohl U. Elevation of plasma viscosity induces sustained NO-mediated dilation in the hamster cremaster microcirculation in vivo. PflugersArch 434: 354-361, 1997. 24. Dempsey JA, Hanson PG, and Henderson KS. Exercise-induced arterial hypoxaemia in healthy human subjects at sea level. J Physiol 355: 161-175, 1984. 25. Doering TJ, Resch KL, Steuernagel B, Brix J, Schneider B, and Fischer GC. Passive and active exercises increase cerebral blood flow velocity in young, healthy individuals. Am J PhysMedRehabilll: 490-493, 1998. 26. Dyken ME, Somers VK, Yamada T, Ren ZY, and Zimmerman MB. Investigating the relationship between stroke and obstructive sleep apnea. Stroke 27: 401-407, 1996. 27. Edwards MR, Martin DH, and Hughson RL. Cerebral hemodynamics and resistance exercise. Med Sci Sports Exerc 34: 1207-1211, 2002.  47  28. Endo T, Imaizumi T, Tagawa T, Shiramoto M, Ando S, and Takeshita A. Role of nitric oxide in exercise-induced vasodilation of the forearm. Circulation 90: 2886-2890, 1994. 29. Fahlman A, Jackson S, Terblanche J, Fisher JA, Vesely A, Sasano H, and Myburgh KH. A simple breathing circuit to maintain isocapnia during measurements of the hypoxic ventilatory response. Respir Physiol Neurobiol 133: 259-270, 2002. 30. Fletcher EC. Effect of episodic hypoxia on sympathetic activity and blood pressure. Respir Physiol 119: 189-197, 2000. 31. Fletcher EC, Lesske J, Qian W, Miller CC, 3rd, and Unger T. Repetitive, episodic hypoxia causes diurnal elevation of blood pressure in rats. Hypertension 19: 555-561, 1992. 32. Foster GE, Hanly PJ, Ostrowski M, and Poulin MJ. Effects of continuous positive airway pressure on cerebral vascular response to hypoxia in patients with obstructive sleep apnea. Am J Respir Crit Care Med 175: 720-725, 2007. 3 3. Foster GE, McKenzie DC, Milsom WK, and Sheel AW. Effects of two protocols of intermittent hypoxia on human ventilatory, cardiovascular and cerebral responses to hypoxia. J Physiol 567: 689-699, 2005. 34. Friedman DB, Friberg L, Mitchell JH, and Secher NH. Effect of axillary blockade on regional cerebral blood flow during static handgrip. JAppl Physiol 71: 651-656, 1991. 35. Gabel RA and Weiskopf RB. Ventilatory interaction between hypoxia and [H+] at chemoreceptors of man. J Appl Physiol 39: 292-296, 1975. 36. Garcia N, Hopkins SR, and Powell FL. Intermittent vs continuous hypoxia: effects on ventilation and erythropoiesis in humans. Wilderness Environ Med 11: 172-179, 2000. 37. Giller CA, Giller AM, Cooper CR, and Hatab MR. Evaluation of the cerebral hemodynamic response to rhythmic handgrip. J Appl Physiol 88: 2205-2213, 2000. 38. Gilligan DM, Panza JA, Kilcoyne CM, Waclawiw MA, Casino PR, and Quyyumi AA. Contribution of endothelium-derived nitric oxide to exercise-induced vasodilation. Circulation 90: 2853-2858, 1994. 39. Globus M, Melamed E, Keren A, Tzivoni D, Granot C, Lavy S, and Stern S. Effect of exercise on cerebral circulation. J Cereb Blood Flow Metab 3: 287-290, 1983. 40. Gonzalez-Alonso J, Dalsgaard MK, Osada T, Volianitis S, Dawson EA, Yoshiga CC, and Secher NH. Brain and central haemodynamics and oxygenation during maximal exercise in humans. J Physiol 557: 331-342, 2004.  41. Greenberg HE, Sica A, Batson D, and Scharf SM. Chronic intermittent hypoxia increases sympathetic responsiveness to hypoxia and hypercapnia. J Appl Physiol 86: 298-305, 1999. 42. Haggendal E and Johansson B. Effects of arterial carbon dioxide tension and oxygen saturation on cerebral blood flow autoregulation in dogs. Acta Physiol ScandSuppl 258: 27-53, 1965. 48  43. Hannhart B, Pickett CK, and Moore LG. Effects of estrogen and progesterone on carotid body neural output responsiveness to hypoxia. J Appl Physiol 68: 1909-1916, 1990. 44. He J, Kryger MH, Zorick FJ, Conway W, and Roth T. Mortality and apnea index in obstructive sleep apnea. Experience in 385 male patients. Chest 94: 9-14, 1988. 45. Heckmann JG, Brown CM, Cheregi M, Hilz MJ, and Neundorfer B. Delayed cerebrovascular autoregulatory response to ergometer exercise in normotensive elderly humans. Cerebrovasc Dis 16: 423-429, 2003. 46. Heckmann JG, Hilz MJ, Muck-Weymann M, and Neundorfer B. Transcranial doppler sonography-ergometer test for the non-invasive assessment of cerebrovascular autoregulation in humans. J Neurol Sci 177: 41-47, 2000. 47. Heistad DD and Abboud FM. Dickinson W. Richards Lecture: Circulatory adjustments to hypoxia. Circulation 61: 463-470, 1980. 48. Heistad DD and Kontos HA. Cerebral circulation. In: Handbook of Physiology: The Cardiovascular System, edited by Shepherd JT, Abboud F M and Geiger SR..Bathesda: American Physiological Society, 1983, p. 137-182. 49. Hellstrom G, Fischer-Colbrie W, Wahlgren NG, and Jogestrand T. Carotid artery blood flow and middle cerebral artery blood flow velocity during physical exercise. J Appl. Physiol 81: 413-418, 1996. 50. Herholz K, Buskies W, Rist M, Pawlik G, Hollmann W, and Heiss WD. Regional cerebral blood flow in man at rest and during exercise. J Neurol 234: 9-13, 1987. 51. Heuser JAD, Lassen NA, Nilsson B, Norberg K, and Siesjo BK. Evidence against H+ and K+ as the main factors in the regulation of cerebral blood flow during epileptic dishcharges, acute hypoxemia, amphetamine intoxication, and hypoglycemia. A microelectrode study. In: Ionic Actions on Vascular Smooth Muscle, edited by Betz E. New York: Springer-Verlag, 1976, p. 110-116. 52. Hirshman CA, McCullough RE, and Weil JV. Normal values for hypoxic and hypercapnic ventilaroty drives in man. J Appl Physiol 38: 1095-1098, 1975. 53. Huang SY, Tawney KW, Bender PR, Groves BM, McCullough RE, McCullough RG, Micco AJ, Manco-Johnson M, Cymerman A, Greene ER, and et al. Internal carotid flow velocity with exercise before and after acclimatization to 4,300 m. J Appl Physiol 71: 14691476, 1991. 54. Hupperets MD, Hopkins SR, Pronk MG, Tiemessen IJ, Garcia N, Wagner PD, and Powell FL. Increased hypoxic ventilatory response during 8 weeks at 3800 m altitude. Respir Physiol Neurobiol 142: 145-152, 2004. 55. Iadecola C. Does nitric oxide mediate the increases in cerebral blood flow elicited by hypercapnia? Proc Natl Acad Sci USA 89: 3913-3916, 1992. 56. Ide K, Horn A, and Secher NH. Cerebral metabolic response to submaximal exercise. J Appl Physiol 87: 1604-1608, 1999. 49  57. Ide K, Pott F, Van Lieshout JJ, and Secher NH. Middle cerebral artery blood velocity depends on cardiac output during exercise with a large muscle mass. Acta Physiol Scand 162: 13-20, 1998. 58. Ide K and Secher NH. Cerebral blood flow and metabolism during exercise. Prog Neurobiol 61: 397-414, 2000. 59. Imadojemu VA, Mawji Z, Kunselman A, Gray KS, Hogeman CS, and Leuenberger UA. Sympathetic chemoreflex responses in obstructive sleep apnea and effects of continuous positive airway pressure therapy. Chest 131: 1406-1413, 2007. 60. Imray CH, Myers SD, Pattinson KT, Bradwell AR, Chan CW, Harris S, Collins P, and Wright AD. Effect of exercise on cerebral perfusion in humans at high altitude. J Appl Physiol 99: 699-706,2005. 61. Imray CH, Walsh S, Clarke T, Tiivas C, Hoar H, Harvey TC, Chan CW, Forster PJ, Bradwell AR, and Wright AD. Effects of breathing air containing 3% carbon dioxide, 35% oxygen or a mixture of 3% carbon dioxide/35%) oxygen on cerebral and peripheral oxygenation at 150 m and 3459 m. Clin Sci (Lond) 104: 203-210, 2003. 62. Ingvar DH. Functional landscapes of the dominant hemisphere. Brain Res 107: 181-197, 1976. 63. Insalaco G, Romano S, Salvaggio A, Braghiroli A, Lanfranchi P, Patruno V, Donner CF, and Bonsignore G. Cardiovascular and ventilatory response to isocapnic hypoxia at sea level and at 5,050 m. J Appl Physiol 80: 1724-1730,1996. 64. Iwasaki K, Ogawa Y, Shibata S, and Aoki K. Acute exposure to normobaric mild hypoxia alters dynamic relationships between blood pressure and cerebral blood flow at very low frequency. J Cereb Blood Flow Metab 27: 776-784, 2007. 65. Jansen GF, Krins A, Basnyat B, Odoom JA, and Ince C. The role of the altitude level on cerebral autoregulation in man resident at high altitude. J Appl Physiol, 2007. 66. Jensen JB, Sperling B, Severinghaus JW, and Lassen NA. Augmented hypoxic cerebral vasodilation in men during 5 days at 3,810 m altitude. J Appl Physiol 80: 1214-1218, 1996. 67. Johnston AJ, Steiner LA, Balestreri M, Gupta AK, and Menon DK. Hyperoxia and the cerebral hemodynamic responses to moderate hyperventilation. Acta Anaesthesiol Scand 47: 391-396,2003. 68. Jordan AS, Catcheside PG, O'Donoghue FJ, and McEvoy RD. Long-term facilitation of ventilation is not present during wakefulness in healthy men or women. J Appl Physiol 93: 2129-2136,2002. 69. Jordan J, Shannon JR, Diedrich A, Black B, Costa F, Robertson D, and Biaggioni I. Interaction of carbon dioxide and sympathetic nervous system activity in the regulation of cerebral perfusion in humans. Hypertension 36: 383-388, 2000.  50  70. Jorgensen LG, Perko G, and Secher NH. Regional cerebral artery mean flow velocity and blood flow during dynamic exercise, in humans. J Appl Physiol 73: 1825-1830, 1992. 71. Jorgensen LG, Perko M, Hanel B, Schroeder TV, and Secher NH. Middle cerebral artery flow velocity and blood flow during exercise and muscle ischemia in humans. J Appl Physiol 72: 1123-1132, 1992. 72. Katayama K, Matsuo H, Ishida K, Mori S, and Miyamura M. Intermittent hypoxia improves endurance performance and submaximal exercise efficiency. High Alt Med Biol 4: 291304, 2003. 73. Katayama K, Sato K, Matsuo H, Ishida K, Iwasaki K, and Miyamura M. Effect of intermittent hypoxia on oxygen uptake during submaximal exercise in endurance athletes. Eur J Appl Physiol 92: 75-83, 2004. 74. Katayama K, Sato Y, Ishida K, Mori S, and Miyamura M. The effects of intermittent exposure to hypoxia during endurance exercise training on the ventilatory responses to hypoxia and hypercapnia in humans. Eur J Appl Physiol Occup Physiol 78: 189-194, 1998. 75. Katayama K, Sato Y, Morotome Y, Shima N, Ishida K, Mori S, and Miyamura M. Intermittent hypoxia increases ventilation and Sa(02) during hypoxic exercise and hypoxic chemosensitivity. J Appl Physiol 90: 1431-1440, 2001. 76. Katayama K, Sato Y, Morotome Y, Shima N, Ishida K, Mori S, and Miyamura M. Ventilatory chemosensitive adaptations to intermittent hypoxic exposure with endurance training and detraining. J Appl Physiol 86: 1805-1811, 1999. 77. Katayama K, Sato Y, Shima N, Qiu JC, Ishida K, Mori S, and Miyamura M. Enhanced chemosensitivity after intermittent hypoxic exposure does not affect exercise ventilation at sea level. Eur J Appl Physiol 87: 187-191, 2002. 78. Katayama K, Shima N, Sato Y, Qiu JC, Ishida K, Mori S, and Miyamura M. Effect of intermittent hypoxia on cardiovascular adaptations and response to progressive hypoxia in humans. High Alt Med Biol 2: 501-508, 2001. 79. Kato M, Roberts-Thomson P, Phillips BG, Haynes WG, Winnicki M, Accurso V, and Somers VK. Impairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnea. Circulation 102: 2607-2610, 2000. 80. Kety SS and Schmidt CF. The Effects Of Altered Arterial Tensions Of Carbon Dioxide And Oxygen On Cerebral Blood Flow And Cerebral Oxygen Consumption Of Normal Young Men. J Clin Invest 27: 484-492, 1948. 81. Kleinerman J and Salvatore MS. Effect of mild steady state exercise on cerebral and general hemodynamics of normal untrained subjects. J Clin Invest 34: 945-956, 1955. 82. Koch A, Ivers M, Gehrt A, Schnoor P, Rump A, and Rieckert H. Cerebral autoregulation is temporarily disturbed in the early recovery phase after dynamic resistance exercise. Clin Auton Res 15: 83-91, 2005.  51  83. Koehle MS, Foster GE, McKenzie DC, and Sheel AW. Repeated measurement of hypoxic ventilatory response as an intermittent hypoxic stimulus. Respir Physiol Neurobiol 145: 33-39,2005. 84. Kolb JC, Ainslie PN, Ide K, and Poulin MJ. Effects of five consecutive nocturnal hypoxic exposures on the cerebrovascular responses to acute hypoxia and hypercapnia in humans. J Appl Physiol 96: 1745-1754, 2004. 85. Kontos HA, Wei EP, Navari RM, Levasseur JE, Rosenblum WI, and Patterson JL, Jr. Responses of cerebral arteries and arterioles to acute hypotension and hypertension. Am J Physiol 234: H371-383, 1978. 86. Krejza J, Siemkowicz J, Sawicka M, Szylak A, Kochanowicz J, Mariak Z, Lewko J, Spektor V, Babikian V, and Bert R. Oscillations of cerebrovascular resistance throughout the menstrual cycle in healthy women. Ultrasound Obstet Gynecol 22: 627-632, 2003. 87. Lassen NA. Cerebral blood flow and oxygen consumption in man. Physiol Rev 39: 183238, 1959. 88. Lassen NA. Control of cerebral circulation in health and disease. Circ Res 34: 749-760, 1974. 89. Lavi S, Gaitini D, Milloul V, and Jacob G. Impaired cerebral C 0 2 vasoreactivity: association with endothelial dysfunction. Am J Physiol Heart Circ Physiol 291: HI 856-1861, 2006. 90. Lavie L. Obstructive sleep apnoea syndrome—an oxidative stress disorder. Sleep Med Rev 7: 35-51,2003. 91. Lavie L, Hefetz A, Luboshitzky R, and Lavie P. Plasma levels of nitric oxide and L arginine in sleep apnea patients: effects of nCPAP treatment. JMol Neurosci 21: 57-63, 2003. 92. Lennox WG and Gibbs EL. The Blood Flow In The Brain And The Leg Of Man, And The Changes Induced By Alteration Of Blood Gases. J Clin Invest 11: 1155-1177, 1932. 93. Linkis P, Jorgensen LG, Olesen HL, Madsen PL, Lassen NA, and Secher NH. Dynamic exercise enhances regional cerebral artery mean flow velocity. J Appl Physiol 78: 1216, 1995. 94. Lugliani R, Whipp BJ, and Wasserman K. A role for the carotid body in cardiovascular control in man. Chest 63: 744-750, 1973. 95. Lusina SJ, Kennedy PM, Inglis JT, McKenzie DC, Ayas NT, and Sheel AW. Longterm intermittent hypoxia increases sympathetic activity and chemosensitivity during acute hypoxia in humans. J Physiol 575: 961-970, 2006. 96. Madsen PL, Sperling BK, Warming T, Schmidt JF, Secher NH, Wildschiodtz G, Holm S, and Lassen NA. Middle cerebral artery blood velocity and cerebral blood flow and 0 2 uptake during dynamic exercise. J Appl Physiol 74: 245-250, 1993.  52  97. Magyar MT, Valikovics A, Czuriga I, and Csiba L. Changes of cerebral hemodynamics in hypertensives during physical exercise. J Neuroimaging 15: 64-69, 2005. 98. Mathew L, Gopinath PM, Purkayastha SS, Sen Gupta J, and Nayar HS. Chemoreceptor sensitivity in adaptation to high altitude. Aviat Space Environ Med 54: 121-126, 1983. 99. McArdle WD, Katch FI, and Katch VL. Exercise physiology: energy, nutrition, and human performance. Baltimore: Lippincott Williams & Wilkins, 2007. 100. McEvoy RD, Popovic RM, Saunders NA, and White DP. Effects of sustained and repetitive isocapnic hypoxia on ventilation and genioglossal and diaphragmatic EMGs. J Appl Physiol S\: 866-875, 1996. 101. Moraine JJ, Lamotte M, Berre J, Niset G, Leduc A, and Naeije R. Relationship of middle cerebral artery blood flow velocity to intensity during dynamic exercise in normal subjects. Eur J Appl Physiol Occup Physiol 67: 35-38, 1993. 102. Ngai AC and Winn HR. Modulation of cerebral arteriolar diameter by intraluminal flow and pressure. Circ Res 11: 832-840, 1995. 103. Nielsen HB, Boushel R, Madsen P, and Secher NH. Cerebral desaturation during exercise reversed by 0 2 supplementation. Am J Physiol 211: H1045-1052, 1999. 104. Nybo L, Moller K, Volianitis S, Nielsen B, and Secher NH. Effects of hyperthermia on cerebral blood flow and metabolism during prolonged exercise in humans. J Appl Physiol 93: 5864,2002. 105. Nybo L and Nielsen B. Middle cerebral artery blood velocity is reduced with hyperthermia during prolonged exercise in humans. J Physiol 534: 279-286, 2001. 106. Ogoh S, Brothers RM, Barnes Q, Eubank WL, Hawkins MN, Purkayastha S, A OY, and Raven PB. The effect of changes in cardiac output on middle cerebral artery mean blood velocity at rest and during exercise. J Physiol 569: 697-704, 2005. 107. Ogoh S, Fadel PJ, Zhang R, Selmer C, Jans O, Secher NH, and Raven PB. Middle cerebral artery flow velocity and pulse pressure during dynamic exercise in humans. Am J Physiol Heart Circ Physiol 288: H1526-1531, 2005. 108. Okabe S, Hida W, Kikuchi Y, Taguchi O, Ogawa H, Mizusawa A, Miki H, and Shirato K. Role of hypoxia on increased blood pressure in patients with obstructive sleep apnoea. Thorax 50: 28-34, 1995. 109. Palmer RM, Ashton DS, and Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature 333: 664-666, 1988. 110. Palomaki H, Partinen M, Juvela S, and Kaste M. Snoring as a risk factor for sleeprelated brain infarction. Stroke 20: 1311 -1315, 1989.  53  111. Peng YJ, Overholt JL, Kline D, Kumar GK, and Prabhakar NR. Induction of sensory long-term facilitation in the carotid body by intermittent hypoxia: implications for recurrent apneas. Proc Natl Acad Sci USA 100: 10073-10078, 2003. 112. Peng YJ and Prabhakar NR. Effect of two paradigms of chronic intermittent hypoxia on carotid body sensory activity. J Appl Physiol 96: 1236-1242; discussion 1196, 2004. 113. Phillips SA, Olson EB, Morgan BJ, and Lombard JH. Chronic intermittent hypoxia impairs endothelium-dependent dilation in rat cerebral and skeletal muscle resistance arteries. Am J Physiol Heart Circ Physiol 286: H388-393, 2004. 114. Placidi F, Diomedi M, Cupini LM, Bernardi G, and Silvestrini M. Impairment of daytime cerebrovascular reactivity in patients with obstructive sleep apnoea syndrome. J Sleep Res 7: 288-292, 1998. 115. Pott F, Jensen K, Hansen H, Christensen NJ, Lassen NA, and Secher NH. Middle cerebral artery blood velocity and plasma catecholamines during exercise. Acta Physiol Scand 158:349-356,1996. 116. Pott F, Knudsen L, Nowak M, Nielsen HB, Hanel B, and Secher NH. Middle cerebral artery blood velocity during rowing. Acta Physiol Scand 160: 251-255, 1997. 117. Pott F, Ray CA, Olesen HL, Ide K, and Secher NH. Middle cerebral artery blood velocity, arterial diameter and muscle sympathetic nerve activity during post-exercise muscle ischaemia. Acta Physiol Scand 160: 43-47, 1997. 118. Pott F, Van Lieshout JJ, Ide K, Madsen P, and Secher NH. Middle cerebral artery blood velocity during intense static exercise is dominated by a Valsalva maneuver. J Appl Physiol 94: 1335-1344, 2003. 119. Poulin MJ, Liang PJ, and Robbins PA. Dynamics of the cerebral blood flow response to step changes in end-tidal PC02 and P02 in humans. J Appl Physiol 81: 1084-1095, 1996. 120. Poulin MJ, Liang PJ, and Robbins PA. Fast and slow components of cerebral blood flow response to step decreases in end-tidal PC02 in humans. J Appl Physiol 85: 388-397, 1998. 121. Poulin MJ and Robbins PA. Indexes of flow and cross-sectional area of the middle cerebral artery using doppler ultrasound during hypoxia and hypercapnia in humans. Stroke 27: 2244-2250, 1996. 122. Poulin MJ, Syed RJ, and Robbins PA. Assessments of flow by transcranial Doppler ultrasound in the middle cerebral artery during exercise in humans. J Appl Physiol 86: 16321637, 1999. 123. Powell FL, Milsom WK, and Mitchell GS. Time domains of the hypoxic ventilatory response. Respir Physiol 112: 123-134, 1998. 124. Prabhakar NR. Oxygen sensing during intermittent hypoxia: cellular and molecular mechanisms. J Appl Physiol 90: 1986-1994, 2001.  54  125. Rasmussen P, Stie H, Nielsen B, and Nybo L. Enhanced cerebral C 0 2 reactivity during strenuous exercise in man. Eur J Appl Physiol 96: 299-304, 2006. 126. Regensteiner JG, McCullough RG, McCullough RE, Pickett CK, and Moore LG. Combined effects of female hormones and exercise on hypoxic ventilatory response. Respir Physiol 82: 107-114, 1990. 127. Richards JC, McKenzie DC, Warburton DE, Road JD, and Sheel AW. Prevalence of exercise-induced arterial hypoxemia in healthy women. Med Sci Sports Exerc 36: 1514-1521, 2004. 128. Rowell LB. Control of Regional Blood Flow During Dynamic Exercise. In: Human cardiovascular control. New York: Oxford University Press, 1993, p. 204-254. 129. Rowell LB. Human circulation: regulation during physical stress. New York Oxford: Oxford University Press, 1986. 130. Rubanyi GM, Romero JC, and Vanhoutte PM. Flow-induced release of endotheliumderived relaxing factor. Am J Physiol 250: HI 145-1149, 1986. 131. Scheinberg P, Blackburn LI, Rich M, and Saslaw M. Effects of vigorous physical exercise on cerebral circulation and metabolism. Am J Med 16: 549-554, 1954. 132. Schmetterer L, Findl O, Strenn K, Graselli U, Kastner J, Eichler HG, and Wolzt M. Role of NO in the 0 2 and C 0 2 responsiveness of cerebral and ocular circulation in humans. Am J Physiol 273: R2005-2012, 1997. 133. Schoene RB, Roach RC, Hackett PH, Sutton JR, Cymerman A, and Houston CS. Operation Everest II: ventilatory adaptation during gradual decompression to extreme altitude. Med Sci Sports Exerc 22: 804-810, 1990. 134. Sechzer PH, Egbert LD, Linde HW, Cooper DY, Dripps RD, and Price HL. Effect of carbon dioxide inhalation on arterial pressure, E C G and plasma catecholamines and 17-OH corticosteroids in normal man. J Appl Physiol 15: 454-458, 1960. 135. Serebrovskaya TV. Comparison of respiratory and circulatory human responses to progressive hypoxia and hypercapnia. Respiration 59: 34-41, 1992. 136. Serebrovskaya TV. Intermittent hypoxia research in the former soviet union and the commonwealth of independent States: history and review of the concept and selected applications. High Alt Med Biol 3: 205-221, 2002. 137. Serrador JM, Picot PA, Rutt BK, Shoemaker JK, and Bondar RL. MRI measures of middle cerebral artery diameter in conscious humans during simulated orthostasis. Stroke 31: 1672-1678,2000. 138. Severinghaus JW, Chiodi H, Eger EI, 2nd, Brandstater B, and Hornbein TF. Cerebral blood flow in man at high altitude. Role of cerebrospinal fluid pH in normalization of flow in chronic hypocapnia. Circ Res 19: 274-282, 1966.  55  139. Shapiro W, Wasserman A J, Baker JP, and Patterson JL, Jr. Cerebrovascular response to acute hypocapnic and eucapnic hypoxia in normal man. J Clin Invest 49: 2362-2368, 1970. 140. Smiesko V, Kozik J, and Dolezel S. Role of endothelium in the control of arterial diameter by blood flow. Blood Vessels 22: 247-251, 1985. 141. Steiner DR, Gonzalez NC, and Wood JG. Interaction between reactive oxygen species and nitric oxide in the microvascular response to systemic hypoxia. J Appl Physiol 93: 14111418,2002. 142. Suzuki YJ, Jain V, Park AM, and Day RM. Oxidative stress and oxidant signaling in obstructive sleep apnea and associated cardiovascular diseases. Free Radio Biol Med 40: 16831692, 2006. 143. Tandon PN. Near infrared spectroscopy: an emerging non-invasive optical imaging technique. Neurol India 47: 83-84, 1999. 144. Thomas SN, Schroeder T, Secher NH, and Mitchell JH. Cerebral blood flow during submaximal and maximal dynamic exercise in humans. J Appl Physiol 67: 744-748, 1989. 145. Toda N, Hatano Y, and Mori K. Mechanisms underlying response to hypercapnia and bicarbonate of isolated dog cerebral arteries. Am J Physiol 257: H141-146, 1989. 146. Van Mil AH, Spilt A, Van Buchem MA, Bollen EL, Teppema L, Westendorp RG, and Blauw GJ. Nitric oxide mediates hypoxia-induced cerebral vasodilation in humans. J Appl Physiol 92: 962-966, 2002. 147. Vizek M, Pickett CK, and Weil JV. Interindividual variation in hypoxic ventilatory response: potential role of carotid body. J Appl Physiol 63: 1884-1889, 1987. 148. Wang JS, Chen LY, Fu LL, Chen ML, and Wong MK. Effects of moderate and severe intermittent hypoxia on vascular endothelial function and haemodynamic control in sedentary men. Eur J Appl Physiol 100: 127-135, 2007. 149. White RP, Vallance P, and Markus HS. Effect of inhibition of nitric oxide synthase on dynamic cerebral autoregulation in humans. Clin Sci (Lond) 99: 555-560, 2000. 150. Xie A, Skatrud JB, Puleo DS, and Morgan BJ. Exposure to hypoxia produces longlasting sympathetic activation in humans. J Appl Physiol 91: 1555-1562, 2001. 151. Xu K and Lamanna JC. Chronic hypoxia and the cerebral circulation. J Appl Physiol 100: 725-730, 2006. 152. Zhang S and Robbins PA. Methodological and physiological variability within the ventilatory response to hypoxia in humans. J Appl Physiol 88: 1924-1932, 2000. 153. Zimmermann C and Haberl RL. L-arginine improves diminished cerebral C 0 2 reactivity in patients. Stroke 34: 643-647, 2003.  56  154. Zobl EG, Talmers FN, Christensen RC, and Baer LJ. Effect of exercise on the cerebral circulation and metabolism. J Appl Physiol 20: 1289-1293, 1965.  57  APPENDIX A - Review of Literature The average human brain weighs 1.4 kg (128), receiving approximately 750 ml/min of blood at rest which accounts for 15% of total body cardiac output (87). Adequate cerebral blood flow is attained by a sound arterial system. The brain is primarily supplied by four arteries: two vertebral and two carotid arteries. The four arteries converge to from the Circle of Willis, an arterial system that allows multiple pathways to supply cerebral tissue, which protects against cerebral ischaemia if one artery becomes blocked. The Circle of Willis diverges to provide perfusion of different parts of the cortex via the anterior, posterior and middle cerebral arteries. Originally thought to remain constant (48), cerebral blood flow is in fact a dynamic system that can experience sudden drastic changes in flow. However, variations regularly occur in response to metabolic, chemical, and pressure influences. Two important homeostatic systems are in place to ensure cerebral tissue is well protected: cerebral autoregulation and cerebral chemoregulation. Cerebral autoregulation maintains a steady cerebral blood flow during hypotension by decreasing resistance, and protects smaller vessels by constriction of feeder arteries during hypertension. Cerebral chemoregulation allows for constant metabolism by increasing flow during hypoxia, and hypercapnia. Given that cerebral tissue is intolerant of ischaemia, an increase in activation is accompanied with an increase in VO2, which is accomplished by increasing blood flow. In this sense, an increase in metabolism is in some way matched with an increase in flow (88). Linkis et al. (93) measured increases in middle cerebral and anterior cerebral artery velocities during right hand contractions, right foot movements, and cycling. The greatest increase in flow was seen in the left middle cerebral artery, and the left anterior cerebral artery during the right hand contraction and right foot movements, respectively. Also, the mean flow velocity in the left and right middle cerebral artery and anterior cerebral artery increased to the same extent during cycling. This suggests that the increase in flow is regional to the arteries which supply the 58  cortical representation of the exercising extremity (93). The hypothesis that increased brain activation is matched with an increase in flow has been supported by others (71).  Regulation of Cerebral Blood Flow As discussed, a variety of influencing factors can lead to changes in brain perfusion; carbon dioxide possibly being the most important (12, 61). Carbon dioxide affects cerebral vessels similarly to how it affects other vascular beds: as a potent vasodilator, where hypercapnia elicits an increase in cerebral perfusion. Additionally, hypoxia elicits cerebral vessel dilation; however, the vasodilating effect of hypoxia is less potent to that of hypercapnia. Conversely, hypocapnia (67), and possibly hyperoxia (11), cause a reduction in CBF. Of the two main chemical stimuli for changes in CBF, C O 2 appears to produce the greatest effects. Ainslie and Poulin (7) measured the acute hypoxic cerebral blood flow response at rest with a hypocapnic, isocapnic, and poikilocapnia background. In comparison to the isocapnic condition, the poikilocapnic condition resulted in V E that elicited a decrease in CBF. It was suggested that poikilocapnia permitted a ventilation induced hypocapnic vasoconstriction (7). Therefore, it was demonstrated that the dilating effects of hypoxia can be attenuated, or even abolished by the constricting effects of hypocapnia. Although the main regulating factor of CBF has been suggested to be extracellular pH, this may not be the only factor controlling cerebral vascular resistance (12). The blood brain barrier readily diffuses  CO2,  where it dissociates to form H and +  HCO3".  It is suggested that the  H produces the relaxant effect of cerebral vasculature. Therefore, C O 2 per se would not be the +  direct regulating factor. Further to this, arterial H would be a poor indication of cerebral vessel +  dilation, as H slowly crosses the blood brain barrier (88, 128). The time course of the response +  of cerebral vessels to a change in pH is quick, where changes in diameter can be observed within  59  10 s (41). The vasoactive response to CO2 is quite significant, with a 30.5% • kPa" change in 1  diameter (125). During exercise, CO2 reactivity incr eased to 40.6% • k P a (125). 1  Cerebral autoregulation is a homeostatic mechanism which retains cerebral blood flow stable in face of changes in arterial pressure. Myogenic properties of cerebral vessels respond to increases in arterial (perfusion) pressure by vasoconstricting and vasodilating during times of sudden hypertension and hypotension, respectively (85). This is an efficient system which maintains a steady cerebral blood flow from arterial pressures of-50-175 mmHg (87, 128). To extend this, Ogoh et al. (2005) measured the effect of increased and decreased cardiac output on cerebral blood flow (106). Decreases and increases in cardiac output at rest by lower body negative pressure and infusion of albumin, respectively, showed a significant linear relationship between middle cerebral arterial blood flow velocity and cardiac output (106).  Cerebral Blood Flow Response to Hypoxia The relationship between arterial oxygen pressure (Pa02) and CBF is curvilinear (15, 48, 128). Maximal vessel dilation in response to hypoxia does not occur at the onset of inspiring hypoxic gas, but rather six minutes after the initiation of hypoxia (139). It is important to note that cerebral autoregulation is abolished once arterial oxygen saturation decreases below 60% (42). However, cerebral autoregulation has also been shown to be impaired at a less severe level of hypoxia (Sa02 ~80%>) (7). Furthermore, hyperoxia has been shown to cause a slight decrease in CBF (80, 92). As mentioned previously, an accompanying hyperventilation induced hypocapnia, can mask any changes in CBF during hypoxia. Huang et al. (53) found no significant difference between internal carotid artery blood flow velocity at rest during normoxia and acute hypoxia; attributing the lack of change to concomitant hypocapnia (53). In contrast, others have shown acute hypoxia to increase CBF when CO2 is uncontrolled, overriding the constricting effects of 60  hypocapnia (15, 80). Also, when isocapnia is maintained, acute hypoxia causes an increase in CBF (7, 48, 119, 128). The mechanisms for cerebral vessel dilation to hypoxia are not fully understood; however, a likely cause stems from hypoxia induced release of adenosine, a strong vasodilator, NO, K , and prostaglandins (48, 128, 146). Although hypoxia may cause acidosis, +  changes in vessel diameter are observed before changes in pH, attributing the change in diameter during hypoxia to a factor other than pH (51). More recently, evidence for the effect of NO on cerebral vessel dilation has gained attention. Human vascular tone is strongly mediated by endothelial derived NO. As such, inhibition of nitric oxide synthesis by infusion of N -monomethyl- -arginine ( L - N M M A ) during L  hypoxia, results in reduced forearm blood flow (13). N O induces vasodilation by working through guanalyl cyclase resulting in relaxation of smooth muscle (13). In addition, the relaxant effect of NO has been suggested to mediate cerebral dilation during acute hypoxia (146). When hypoxia exposure is lengthened and becomes chronic, CBF tends to slowly return to pre-exposure levels. Severinghaus et al. (138) found CBF to increase from rest by 24% and 13%> after 6-12 hours and 3-5 days at altitude, respectively (138). The changes in CBF occurred even though arterial CO2 pressure (PaC02) remained lower than sea level. To extend this, the increase in CBF during chronic hypoxia has been shown to be abolished after three weeks of exposure (151). Possible explanations for the re-normalization of CBF are an increased in oxygen carrying capacity, restoration of tissue oxygen tension, and increased capillary density (151). The hypoxic protocol, whether it be sustained or intermittent, appears to be important in the physiological changes that result, where episodes of hypoxia interspersed with reoxygenation incur a greater magnitude in the physiological response, which will be discussed below (33, 112). Prolonged hypoxia may differ in the CBF response to acute hypoxia, due to changes that occur in the cerebrospinal fluid (CSF). Acute exposure will decrease PaC02, with a 61  similar decrease in CSF PCO2, therefore increasing CSF pH. However, prolonged hypocapnia which accompanies prolonged hypoxia eventually normalizes CSF pH, thereby stabilizing CBF to pre-hypoxia values (138)  Intermittent Hypoxia and Cerebral Blood Flow Intermittent hypoxia (IH) refers to transient episodes of hypoxia. These environments are voluntarily experienced by mountaineers and athletes as a training regimen, and free-divers. Also, involuntary recurrent hypoxia is experienced in pathophysiological conditions such as sleep apnea, chronic obstructive pulmonary disease, and apneas in infants. Depending on the condition, hypoxic episodes can range from seconds to days (124). IH is used in the laboratory as a model of these preceding conditions in order to understand the pathophysiological changes inherent to the condition. Research has shown that IH causes many different physiological changes, many of which are detrimental to health. Some examples include elevated sympathetic nervous activity (95), hypertension (31), and stroke (26, 110). Obstructive sleep apnea, where cessation of breathing occurs during sleep as a consequence of an obstructed airflow, is an important health concern with high mortality (44). The increased incidence of stroke in patients with sleep apnea was suggested to be a consequence of the episodic hypoxia and not the concurrent hypertension or obesity, which often accompanies obstructive sleep apnea (79). Kato et al. (79) tested endothelial function in obstructive sleep apnea patients and matched controls. The results show that those patients with obstructive sleep apnea had a severely blunted response to acetylcholine, an endotheliumdependent vasodilator, when compared to matched controls (79). The authors suggested the mechanism to be attributed to a defect in the biosynthesis of nitric oxide from L-arginine (79). Also, Foster et al. (32) measured the CBF response to acute hypoxia in sleep apnea patients before and after CPAP therapy. Although the sleep apnea patients showed an impaired C B F 62  response, following CPAP therapy the CBF response was similar to those of control subjects. In the rat model, Phillips et al. (113) measured the vasodilator response to acute hypoxia in cerebral and limb arteries, following IH. Experimental male rats were exposed to IH (10% fraction of inspired oxygen for 1 min at 4 min intervals, 12 h/day) for 14 days. After the intermittent hypoxic protocol, the middle cerebral and gracilis arteries were removed in order to test vasodilator response to reduced oxygen. Both the middle cerebral and gracilis arteries' vasodilator response to acute hypoxia were almost completely abolished following IH (113). It was suggested that the mechanism for the reduced response to acute hypoxia was most likely due to the endothelium dependent relaxation rather than a decreased sensitivity to nitric oxide. Recently, our laboratory tested the sensitivity of cerebral oxygenation in the human model following IH. Human subjects underwent either a long-duration (30 min 12% 0 ) or 2  short-duration IH protocol (5 min 12% O2 at 5 min intervals), for 10 days. Cerebral sensitivity (A cerebral tissue oxygenation/A SaC^) was significantly lower by the end of the IH protocol in both groups; however, the response reached greater magnitude in the short-duration group. These findings support the study by Phillips et al. (113) and suggest cerebral vascular dysregulation following IH (33). The Foster et al. (33) study measured cerebral oxygenation via near-infrared spectroscopy. Near-infrared spectroscopy measures differences in chromofore concentrations which is an indication of oxyhaemoglobin and deoxyhaemoglobin (143); however, it does not provide an actual indication of flow. Therefore, cerebral perfusion could not be assessed. We recently followed this study by measuring the effects of IH on cerebral blood flow velocity, a better indication of cerebral perfusion. The cerebral blood flow velocity response to acute hypoxia was measured in eight subjects who underwent 10 consecutive days of IH (12%> O2 for 5 min at 5 min intervals, 1 h/day). Results showed a blunted cerebral blood flow response to acute hypoxia. This would suggest cerebral dysregulation, and upon review of the literature it is  63  cautiously suggested to be due to a defect in the vasodilating effect of NO. Taken with the available literature, IH appears to cause a blunted cerebral vasodilator response to acute hypoxia. In contrast, Kolb et al. (84) found an increase in the cerebral response to acute hypoxia following IH. Differences in methodologies must be considered, as this study defined IH as a fraction of inspired oxygen of-13.8%, 8 h/night, for 5 nights. As discussed earlier, the cycling between normoxia and hypoxia may be the cause for many of the differences in physiological variables. In addition, the total amount of hypoxia experienced differs between the Foster et al. (33) and Kolb et al. (84) studies (e.g. 40 hrs (84) vs. 5 hrs (33)). Further to the increase in cerebral sensitivity to acute oxygen, Kolb et al. (84) found an increase in the cerebral sensitivity to acute hyperoxic hypercapnia, following the intermittent hypoxic protocols. In fact, cerebral sensitivities to oxygen and carbon dioxide, as well as acute mountain sickness scores, were comparable to results previously published with chronic sustained hypoxia. This might suggest that although Kolb and his colleagues (84) defined their protocol as IH, it may be more suitable to in fact consider their protocol as continuous. Recently, Ainslie et al. (2) found an increase in the CBF response to acute poikilocapnic hypoxia following 10-12 days of IH (12%> O2 at 5 min intervals, 90 min/day). Although there are methodological shortcomings of their study (see Discussion), they suggest that IH may aid in pre-acclimatization. Placidi et al. (114) measured cerebrovascular sensitivity to a breath-hold, in sleep apnea patients and healthy controls. With the use of a 30 second breath-hold, cerebrovascular reactivity to CO2 was measured in the morning and afternoon. The breath-hold index (obtained by dividing the percent increase in CBF during the breath-hold by the duration of the breath-hold) was significantly lower in the patient group compared to the control group (114). This finding suggests cerebral dysregulation to CO2 in individuals who experience IH, and further contests the results from Kolb et al. (84). Further, both patient and control groups experienced an increase in the breath-hold index in the afternoon compared to the morning trial. Authors of the study 64  suggest that this is due to overnight relative hypercapnia which causes transient hyposensitivity of cerebrovascular chemoreceptors (114). It should be noted that arterial oxyhaemoglobin saturation was not measured during the breath-hold; therefore, changes in CBF to possible oxyhaemoglobin desaturation could not be assessed. Similar to the proposed mechanism to cerebral dysregulation to acute hypoxia following IH, N O appears to be involved in endothelial dysfunction during hypercapnia. This hypothesis was tested in patients with endothelial dysfunction, as well as controls (89). Hypercapnia was induced with the inhalation of 5% CO2, 95% O2 for 6 min both with and without infusion of sodium nitroprusside. In comparison to the control group, the patient group showed a compromised cerebral chemoregulation; furthermore, the difference between the control and patient group was abolished in the sodium nitroprusside trial. Vasoreactivity remained unaffected to sodium nitroprusside infusion in the patient group, proposing that endothelial dysfunction blunts nitric oxide release during carbon dioxide stress (89). Although IH has been shown to cause increased baseline M A P in the animal model (41), this is not consistent for humans (78, 95). Katayama et al. (78) exposed 14 subjects to a simulated altitude of 4500 m, for 1 hr/day, for seven days. Despite the fact that systolic and diastolic blood pressure sensitivities to acute hypoxia increased, resting M A P was unchanged. Although clinical populations (e.g. sleep apnea) most often have higher resting blood pressures (9), some have suggested the mechanistic explanation does not appear to be attributed to the recurrent hypoxia episodes (108). In contrast, Xie et al. (150) exposed subjects to 20 min of isocapnic hypoxia and 20 min of normoxic hypercapnia while continued measurement of muscle sympathetic nerve activity was conducted at the peroneal nerve. Upon withdrawal of the isocapnic hypoxia, sympathetic activity remained elevated, whereas sympathetic activity returned to baseline soon after cessation of the normoxic hypercapnic stimulus. This implies the importance of hypoxia in the sustained elevation of sympathetic activity, and may contribute to 65  the elevated resting blood pressures observed in sleep apnea patients (150). These results may suggest that alterations in blood pressure are not observed in most human studies due to the length of the protocol.  Cerebral Blood Flow during Exercise Although there is evidence for no change (131, 154), or a decrease (39, 81) in CBF during exercise, there is consistent support for an increase in CBF during exercise (19, 25, 34, 37, 45,46, 49, 53,56-58,70,71,93,96, 101, 105, 107, 115-118, 122, 144). Early investigations failed to show an increase in CBF during exercise (81, 131); however, more recent work has shown a significant increase (19, 45, 56, 60, 71, 93, 105, 107, 115-117) that is intensity dependent (70, 101) and contingent on the artery being insonated (49). Increases in CBF are observed up to an exercise intensity of ~60%VO2max, after which the exercise induced hyperventilation causes a decrease in CBF (93), sometimes below baseline values (49, 101). The initial increase in CBF in response to exercise has been suggested to be due to the increase in metabolism. Herholz et al. (50) measured the CBF response to cycling at 25 and 100 watts. They showed a greater increase in CBF during cycling at 100 watts when compared to cycling at 25 watts; attributing the increase to increased neuronal activity and brain metabolism. This has further been suggested by Linkis et al. (93), who measured the increase in the middle cerebral artery and anterior carotid artery blood flow velocity during right hand contractions, right foot movements, and cycling. The middle cerebral artery and anterior carotid artery showed the greatest increases in flow during right hand and right foot contractions, respectively. Further to this, the mean flow velocity increased similarly in the right and left middle and anterior carotid arteries during cycling. This suggests that it is those arteries that supply the cortical representation of the exercising limb, which experience the greatest increase in flow (93). However, cerebral autoregulation has been suggested to be disturbed upon cessation of exercise 66  of dynamic (49, 82) and static exercise (27). Both increases and decreases have been observed during the post-exercise period; however, the meaningfulness of the change is unclear (82).  Regulation of Cerebral Blood Flow during Exercise Similar to the abundant support for C O 2 to be a major contributor to CBF at rest, C O 2 also appears to play a major role in regulating CBF during exercise (49, 61, 101, 104, 105, 125). Many of these studies are correlative in nature, where an increase in ventilation, and thus a decrease in end tidal P C O 2 (PETCO2) is accompanied with a decrease in CBF (49, 69). Moderate intensity cycle exercise has been shown to increase middle cerebral arterial blood flow velocity by 21%; however, once correcting for P E T C O 2 , the increase in blood flow velocity was eliminated (16). Although there is strong support for PaCC>2 to be a major player in the regulation of CBF during exercise, some suggest that it has been overemphasized (25, 46, 106). Heckmann et al. (46) measured PaCC>2 during cycling at 75-100 W for three minutes. Middle cerebral arterial blood flow velocity increased before any increase in PaCCh was noted, suggesting that the increase in blood flow, at least in the early stages of exercise, is strongly influenced by other factors than C O 2 (46). Similarly, cycling at three different intensities resulted in increases in M C A V , however, end tidal P C 0 did not change (70). 2  Increased cardiac output to working muscles, decreased cognitive function (17), possible arterial hypoxemia (24, 127), and decreased oxyhaemoglobin binding due to a lowered pH during exercise might suggest that the brain is compromised during exercise. Furthermore, increases in CBF appear to only occur up to a of 50-60% V02max, and further increases in exercise intensity are actually accompanied with decreases in CBF (49, 101, 144). Given this information, it may suggest that the brain is compromised during high-intensity exercise; however, Pa02 is most often unchanged in the general population during exercise (18), 67  suggesting that it does not commonly contribute to the regulation of CBF during exercise. Also, tissue oxygen extraction increases at high intensity exercise (40) and the increase in CBF surpasses the oxygen demand (56) implying that the brain is well protected during exercise (40). It should be noted that oxygen supplementation during high intensity exercise can blunt cerebral desaturation, and possibly improve performance in high-level athletes (103). However, this study consisted of elite rowers who are more likely to experience exercise induced arterial hypoxemia; therefore it is intuitive that oxygen supplementation by these athletes would attenuate cerebral desaturation. For this reason, generalization of the results to the general population is problematic. The increase in M C A V during exercise has further been attributed to M A P (56, 97, 104, 116). Exercise at 30% and 60% VC^max produces similar increases in M C A V and M A P , although PaCC>2 remains unchanged from rest (56). This increase in M C A V may be a result of an inability for cerebral autoregulation to dampen the drastic increases in perfusion pressure. When exercise involves the use of a large muscle mass, the contribution of cardiac output becomes more important to the regulation of CBF. Ide et al. (57) tested this hypothesis by pharmacologically inhibiting the increase in cardiac output during hand contractions and cycle ergometry. It was found that inhibiting the increase in cardiac output only decreased M C A V during cycling, and not during hand contractions (57). The authors of that study attributed the decrease in M C A V to competition between the working muscle mass and cerebral tissue. The importance of cardiac output to CBF appears to be attributed to stroke volume, as heart rate does not affect M C A V during exercise (14). However, increases in CBF have been observed without a concurrent increase in cardiac output (39). Furthermore, at maximal exercise, M C A V quickly peaks, then quickly declines, whereas cardiac output remains elevated (40). This suggests other factors aside from cardiac output that contribute to CBF regulation during maximal exercise (40). Determining the relative contribution of each regulating factor to CBF is difficult due to 68  contradictory evidence, however, given this, cerebral autoregulation appears to maintain protection of cerebral tissue in healthy individuals (19).  Exercise and Nitric Oxide Nitric oxide (NO), a key biological messenger for the vasodilation of vessels, should be considered as a possible mechanistic explanation to vascular dysfunction in response to IH. Produced in endothelial cells from L-arginine, N O diffuses locally to smooth muscle to bring about vessel relaxation (109). The increase in flow during exercise, increases shear stress of vessels walls, which in turn initiates vasodilation through the release of NO (130). Inhibition of NO by administration of L - N M M A leads to a reduced arm blood flow during exercise; attributing at least 26% of vascular resistance during exercise to N O production (38). Determining the relative contribution of NO to increased blood flow (smooth muscle relaxation) during exercise is arduous as vascular relaxation can be caused by various physiological mechanisms, such as withdrawal of autonomic control, release of metabolites, and mechanical factors. However, cerebral autoregulation does appear to be regulated by NO. White et al. (149) found cerebral autoregulation to be significantly delayed after infusion of L - N M M A , suggesting that depressing NO reduces the speed of cerebral autoregulation (149). Therefore, the possibility exists that IH may decrease the bioavailability of NO for cerebral circulation during exercise.  69  APPENDIX B - Individual Raw Data Table 10. Individual subjects' anthropometric, pulmonary function, and transcranial Doppler ultrasound insonation depth characteristics. B M I = body mass index Subject 1 2 3 4 5 6 7 8 9  Age  Height  Mass  BMI  (yrs) 25 22 23 26 19 24 24 22 27  (cm) 166 184 181 186 181 184 182 174 187  (kg) 60 84 74 72 76 84 84 67 94  (kg/m ) 21.8 24.8 22.6 20.8 23.2 24.8 25.4 22.1 26.9  FVC 2  (L) 4.25 5.93 5.28 5.27 5.79 6.31 5.79 3.78 6.35  FEVLQ  FEVLO/FVC  FEVLO/FVC  (%) 77.6 81.8 86.2 87.9 84.6 78.3 83.2 92.6 79.5  (% predicted) 91.2 95.7 100.6 106.7 98.7 91.6 97.2 107.3 96.8  (L) . 3.3 4.85 4.55 4.63 4.9 4.94 4.82 3.5 5.05  MCAV depth (cm) 5.3 5.0 5.0 5.1 5.0 5.0 5.0 5.3 5.2  Table 11. Individual subject baseline ventilation ( V E ) , mean arterial blood pressure (MAP), and mean middle cerebral arterial blood flow velocity (MCAVm) prior to the acute hypoxic response and exercise, PRE-IH and POST-IH. A H R = baseline ventilation prior to A H R ; Exercise = baseline ventilation prior to exercise; PRE-IH = experimental day before intermittent hypoxia; POST-IH = experimental day after intermittent hypoxia. • 1 2 3 4 5 6 7 8 9  AHR Exercise AHR Exercise AHR Exercise AHR Exercise AHR Exercise AHR Exercise AHR Exercise AHR Exercise AHR Exercise  V E (L/min) PRE-IH POST-IH 4.4 8.3 4.4 4.3 11.2 9.8 14.1 11.3 10.7 7.3 10.9 16.3 9.3 10.4 10.8 8.7 6.0 9.9 9.9 11.3 10.4 10.6 11.7 11.0 10.7 9.7 11.3 12.0 8.5 6.4 11.1 10.1 10.7 7.7 11.2 11.6  MAP (mmHg) PRE-IH POST-IH 89.3 100.1 98.0 100.8 97.2 87.4 90.4 87.9 90.6 97.0 89.7 93.9 89.4 89.8 97.2 93.0 93.0 87.5 92.8 95.9 100.2 105.3 101.6 100.4 95.9 106.5 105.9 87.8 82.3 87.1 97.3 83.7 87.7 99.6 97.0  MCAVm (cm/s) PRE-IH POST-IH 72.6 80.0 81.7 74.4 53.3 53.7 58.2 48.3 70.3 72.0 68.9 56.1 57.2 58.5 58.7 56.9 61.4 67.3 62.2 52.4 62.5 62.9 52.8 58.7 78.1 77.7 76.4 78.8 68.0 70.9 66.3 66.8 53.3 50.6 54.7 49.6  70  Table 12. The effect of acute hypoxia on ventilatory, cardiovascular and cerebrovascular parameters before and after intermittent hypoxia in each subject. F i 0 2 = fraction of inspired oxygen; SaC>2 = oxyhaemoglobin saturation; V E = minute ventilation; M C A V m = mean middle cerebral arterial blood flow velocity; M A P = mean arterial blood pressure; HR = heart rate; Q = cardiac output; PRE-IH = experimental day before intermittent hypoxia; POST-IH = experimental day after intermittent hypoxia. F i 0 (%) POST-IH -8.1 -10.7 -11.5 -8.8 -9.3 -8.4 -9.6 -9.0 -8.6 2  Subject 1 2 3 4 5 6 7 8 9  PRE-IH -8.4 -8.9 -9.4 -10.8 -10.0 -9.6 -9.3 -8.8 -8.6  S a 0 (%) PRE-IH POST-IH -17.7 -20.8 -18.3 -18.6 -16.4 -17.7 -18.1 -16.7 -21.4 -17.6 -20.2 -19.6 -19.2 -19.1 -14.8 -18.8 -16.5 -16.3 2  V E (L/min) PRE-IH 8.7 4.4 3.4 4.5 7.6 3.0 7.6 8.9 5.0  POST-IH 18.6 6.7 9.0 2.9 6.7 8.0 5.7 5.3 5.9  M C A V m (cm/s) PRE-IH 21.9 -9.9 10.1 7.0 4.7 3.7 0.6 -6.3 3.0  POST-IH 9.2 0.1 0.3 5.8 -1.1 7.3 2.7 7.1 1.6  M A P (mmHg) PRE-IH 8.1 -9.2 8.9 7.4 2.2 -0.8 3.1 -5.5 0.8  POST-IH -2.0 1.6 3.4 10.3 2.6 0.8 -1.9 5.9 -4.6  HR (bpm) PRE-IH 25.4 12.3 19.8 13.2 10.4 16.4 10.8 14.5 7.6  POST-IH 6.9 13.4 23.1 6.8 11.2 11.4 17.1 18.1 6.7  Q (L/min) PRE-IH 1.6 1.4 2.2 1.0 1.0 1.9 1.6 1.0 1.2  POST-IH 0.0 1.5 2.2 0.5 1.0 1.5 2.0 1.4 1.4  Table 13. Effect of exercise intensity on ventilation ( V E ) before (PRE-IH) and after (POST-IH) intermittent hypoxia. Values are in L/min. Subject 1 2 3 4 5 6 7 8 9  PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH  50 W 9.5 10.0 27.7 25.1 30.1 25.1 25.0 24.0 17.4 21.8 26.4 26.2 24.0 23.2 33.1 24.0 27.8 21.7  100 W 13.7 17.4 43.2 29.3 39.2 34.4 30.9 36.0 27.1 34.1 39.6 34.8 33.8 32.6 39.7 34.2 38.4 38.3  150 W 22.9 24.5 54.9 43.0 64.8 50.5 49.4 51.1 38.3 48.3 53.8 55.2 49.3 53.1 48.1 50.4 50.6 48.0  recovery 1 20.0 22.3 28.2 28.1 45.3 38.7 36.1 37.1 24.1 28.2 42.8 40.3 34.4 30.8 32.2 34.1 33.1 36.8  recovery2 16.1 15.3 27.8 16.3 26.1 20.4 20.2 21.7 14.0 18.6 32.1 20.1 19.8 17.9 28.9 24.1 22.2 21.3  recovery3 12.0 8.9 15.1 14.3 19.2 15.8 16.1 17.2 11.4 12.5 19.7 19.7 16.2 13.1 13.2 12.8 17.4 15.5  recovery4 7.2 9.0 15.5 16.0 20.5 12.2 13.0 14.9 9.2 13.2 17.8 14.6 16.0 12.5 19.5 12.5 15.9 16.7  recovery5 5.8 8.3 15.1 13.4 15.7 13.1 11.9 11.5 10.5 13.3 16.1 14.3 14.6 12.4 14.8 11.4 16.4 13.6  Table 14. Effect of exercise intensity on mean arterial blood pressure (MAP) before (PRE-IH) and after (POST-IH) intermittent hypoxia. Values are in mmHg. 50 W 100 W 150 W recovery 1 recovery 2 recovery3 recovery4 recovery 5 Subject 1 PRE-IH 121.6 111.5 104.5 106.9 124.7 100.8 95.9 POST-IH 103.7 139.3 109.0 91.7 90.8 87.5 86.3 2 PRE-IH 97.7 107.8 114.0 92.5 99.7 94.0 95.8 POST-IH 95.2 109.3 103.2 97.6 103.9 98.2 101.0 93.8 94.8 97.4 105.4 114.4 98.8 3 PRE-IH 97.6 99.2 100.0 95.5 POST-IH 108.2 113.0 116.6 98.6 97.4 100.4 102.1 99.6 4 PRE-IH 105.0 114.5 117.9 96.6 94.1 91.4 92.4 93.6 POST-IH 106.8 116.8 93.4 111.2 92.7 92.5 107.4 92.8 93.7 93.3 5 PRE-IH 96.1 99.3 97.7 96.3 96.9 96.1 POST-IH 94.2 104.5 115.6 95.6 107.1 105.5 104.9 109.9 109.1 6 PRE-IH 115.4 115.7 128.3 POST-IH 108.7 104.4 106.2 105.5 108.8 7 PRE-IH 117.3 127.9 123.4 100.5 102.6 102.3 POST-IH 113.1 113.2 129.2 96.8 99.5 82.0 91.7 105.2 107.4 93.4 87.9 86.8 8 PRE-IH 96.1 77.1 80.4 78.5 77.5 POST-IH 86.8 101.0 123.5 86.8 99.2 99.2 101.1 99.5 PRE-IH 117.2 114.3 114.6 99.9 9 93.2 93.5 90.7 POST-IH 100.4 107.7 107.5 90.2 87.3  Table 15. Effect of exercise intensity on mean middle cerebral arterial blood flow velocity (MCAVm) before (PRE-IH) and after (POST-IH) intermittent hypoxia. Values are in cm/s. subject 1 2 3 4 5 6 7 8 9  4^  PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH  50 W 106.0 94.2 51.2 67.2 77.1 73.8 59.2 56.7 81.6 55.5 58.6 64.2 82.9 80.5 58.0 70.7 63.6 54.4  100 W 107.9 97.5 49.6 65.5 83.0 71.2 61.2 57.7 77.1 52.9 58.8 61.6 78.3 83.4 79.1 73.5 58.4 58.0  150 W 103.7 93.3 56.4 61.4 81.1 76.3 63.1 61.4 79.5 74.9 59.6 63.3 79.7 79.7 79.3 74.6 59.3 59.9  recoveryl 103.8 83.0 47.1 54.6 74.5 65.9 56.6 59.3 57.3 59.0 53.4 52.3 73.9 80.1 96.9 74.5 53.2 46.8  recovery2 80.3 58.2 43.4 53.9 67.7 65.7 49.6 46.9 62.9 62.5 43.0 49.9 66.0 70.9 62.2 56.5 50.7 43.3  recovery3 77.0 69.0 45.1 53.5 66.9 62.7 53.2 49.5 71.2 63.8 43.5 53.0 64.6 67.3 62.7 49.2 49.7 51.4  recovery4 91.6 92.2 51.8 53.7 68.4 63.7 54.8 50.0 68.5 68.4 46.2 52.8 71.3 73.6 58.8 64.1 51.0 49.6  recovery5 89.8 84.0 49.3 56.6 70.0 66.4 57.8 52.1 70.4 66.0 45.5 54.9 66.4 70.2 64.5 64.3 56.0 49.7  Table 16. The ventilatory response to hypercapnia (5% CO2) at rest and during exercise before (PRE-IH) and after (POST-IH) intermittent hypoxia. Values are in L/min. subject 1 2 3 4 5 6 7 8 9  PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH  rest 6.6 7.9 20.2 18.9 22.9 16.2 16.2 18.4 12.2 16.9 22.1 16.0 16.8 15.6 14.9 18.5 15.2 16.5  50 W 14.9 20.7 52.1 39.7 • 49.8 44.3 34.7 37.2 33.4 47.7 42.5 40.6 46.7 41.6 36.4 39.3 47.9 47.3  100 W 27.8 33.4 77.7 54.7 71.8 61.5 49.9 59.7 49.6 63.8 59.4 63.0 62.6 65.3 56.3 55.0 60.0 67.6  150 W 39.0 46.2 94.1 72.2 97.9 85.3 79.8 116.5 68.8 82.1 92.1 94.3 94.5 92.3 68.0 67.2 80.9 90.5  75  Table 17. The mean arterial blood pressure (MAP) response to hypercapnia (5% CO2) at rest and during exercise before (PRE-IH) and after (POST-IH) intermittent hypoxia. Values are in mmHg. subject 1 2 3 4 5 6 7 8 9  PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH  rest 101.3 101.9 91.0 88.0 95.2 102.1 92.4 98.9 92.5 91.1 107.1  50 W 114.4 112.7 103.0 100.9 104.5 116.8 109.0 113.6 97.8 100.9 122.0  100 W 129.5 134.0 111.7 106.4 110.8 123.0 113.0 114.7 105.9 109.3 125.4  150 W  108.5 104.8 96.9 90.7 105.1 96.7  123.3 114.0 100.1 95.4 123.3 104.3  122.1 122.2 113.7 113.5 124.1 115.6  133.5 129.8 125.0 115.0 110.7 102.1  153.7 116.6 114.5 122.0 119.6 118.6 112.9 110.6 114.7 134.0  76  Table 18. The mean middle cerebral arterial blood flow velocity (MCAVm) response to hypercapnia (5% CO2) at rest and during exercise before (PRE-IH) and after (POST-IH) intermittent hypoxia. Values are in cm/s. subject 1 2 3 4 5 6 7 8 9  PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH PRE-IH POST-IH  rest 100.8 83.1 57.9 63.0 78.4 75.1 63.5 63.9 74.4 66.9 64.5 63.6 85.8 88.7 77.8 79.1 68.3 59.8  50 W 125.4 109.0 66.3 77.8 84.3 87.9 75.5 78.2 90.0 75.4 78.5 70.4 96.4 94.3 82.9 83.1 84.4 71.9  100 W 146.7 133.3 75.7 82.4 97.3 94.4 83.5 86.6 100.9 94.5 88.1 77.0 107.7 115.6 103.9 105.6 89.6 83.9  150 W 157.9 150.2 84.5 92.5 107.1 103.7 94.2 91.7 113.6 112.4 97.3 88.2 115.8 124.3 118.4 110.1 90.2 85.4  APPENDIX C - UBC Research Ethics Board's Certificate of Approval  The University of British Columbia Office of Research Services Clinical Research Ethics Board - Room 210, 828 West 10th Avenue, Vancouver, BC V5Z 1L8  UBC  ETHICS CERTIFICATE OF EXPEDITED APPROVAL: RENEWAL WITH AMENDMENTS TO THE STUDY PRINCIPAL INVESTIGATOR: William Sheel  UBC CREB NUMBER: H05-70517  DEPARTMENT:  INSTITUTION(S) WHERE RESEARCH WILL BE CARRIED OUT: | Institution I Point Grey Site UBC  Site  |  Other locations where the research will be conducted:  N/A CO-INVESTIGATOR(S): Meaghan MacNutt Jordan Querido SPONSORING AGENCIES: Natural Science Engineering Research Council - "Cerebral and Cardio-Ventilatory Responses to Short Duration Intermittent Hypoxia" PROJECT TITLE: Cerebral and Cardio-Ventilatory Responses to Exercise Following Intermittent Hypoxia  The current UBC CREB approval for this study expires: January 12, 2008 AMENDMENT(S): iDocument Name  Protocol: Protocol version 1 Consent Forms: Consent form version 3  | Version |  Date  |  AMENDMENT APPROVAL DATE: January 12, 2007  version November 1 24,2006 version January 1, 2007 3  Advertisements: Version November 1 24,2006 Questionnaire, Questionnaire Cover Letter, Tests: January 1, N/A PAR-Q 2002 Recruit flyer version 1  CERTIFICATION: In respect of clinical trials: 1. The membership of this Research Ethics Board complies with the membership requirements for Research Ethics Boards defined in Division 5 of the Food and Drug Regulations. 2. The Research Ethics Board carries out its functions in a manner consistent with Good Clinical Practices. 3. This Research Ethics Board has reviewed and approved the clinical trial protocol and informed consent form for the trial which is to be conducted by the qualified investigator named above at the specified clinical trial site. This approval and the views of this Research Ethics Board have been documented in  79  

Cite

Citation Scheme:

    

Usage Statistics

Country Views Downloads
United States 7 0
China 7 20
Canada 6 0
United Kingdom 5 0
Germany 3 0
Netherlands 1 0
City Views Downloads
Vancouver 6 0
Shenzhen 5 20
London 4 0
Ashburn 3 0
Unknown 3 0
Washington 2 0
Beijing 2 0
Wilmington 1 0
High Wycombe 1 0
Maastricht 1 0
Phoenix 1 0

{[{ mDataHeader[type] }]} {[{ month[type] }]} {[{ tData[type] }]}
Download Stats

Share

Embed

Customize your widget with the following options, then copy and paste the code below into the HTML of your page to embed this item in your website.
                        
                            <div id="ubcOpenCollectionsWidgetDisplay">
                            <script id="ubcOpenCollectionsWidget"
                            src="{[{embed.src}]}"
                            data-item="{[{embed.item}]}"
                            data-collection="{[{embed.collection}]}"
                            data-metadata="{[{embed.showMetadata}]}"
                            data-width="{[{embed.width}]}"
                            async >
                            </script>
                            </div>
                        
                    
IIIF logo Our image viewer uses the IIIF 2.0 standard. To load this item in other compatible viewers, use this url:
http://iiif.library.ubc.ca/presentation/dsp.831.1-0077046/manifest

Comment

Related Items