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Intermittent hypoxia : activation of the sympathetic nervous system 2005

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I N T E R M I T T E N T H Y P O X I A : A C T I V A T I O N O F T H E S Y M P A T H E T I C N E R V O U S S Y S T E M by Sarah-Jane C. Lusina Honours Kinesiology, University of  Western Ontario, 2003 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS OF FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE STUDIES (HUMAN KINETICS) THE UNIVERSITY OF BRITISH COLUMBIA August, 2005 © Sarah-Jane C. Lusina, 2005 A B S T R A C T BACKGROUND: Individuals with obstructive sleep apnea (OSA) are reported to have elevated muscle sympathetic nerve activity (MSNA) . In this complicated pathological condition numerous factors  can be implicated in the elevated sympathetic activity; however periodic exposures to hypoxia appear to be the primary cause. In laboratory interventions with healthy humans, it is well documented that acute hypoxia increases M S N A , which persists after  removal of  the hypoxic stimulus. The effect  of  long term exposure of  to intermittent hypoxia (IH) on M S N A is unknown. PURPOSE: The present study was undertaken to address the effect  of  long term IH on MSNA during an acute hypoxic exposure and during the following  normoxic recovery period. Concurrent vastus lateralis oxygenation, cerebral oxygenation, ventilatory and cardiovascular measurements were acquired to examine the relationship between the various physiological systems and how they are altered in response to IH. HYPOTHESIS: Ten days of  IH will augment the rise in MSNA during hypoxia and recovery. METHODS: Eleven healthy males underwent two experimental sessions, consisting of  4 stages: 10 minutes baseline, 5-7 minutes hypoxic ventilatory response (HVR), 20 minutes isocapnic hypoxia (80% arterial oxygen saturation; SaCh), and 20 minutes normoxic recovery. Experimental days were separated by 10 days of  IH where 1 hour of  isocapnic hypoxia (SaC>2 = 80%) was administered. During both experimental sessions the following  parameters were collected: 1) MSNA was acquired from  peroneal nerve recordings. Total MSNA was calculated as the product of  burst frequency  and burst amplitude; 2) blood pressure (BP); 3) heart rate (HR) was acquired from  electrocardiogram; 4) vastus lateralis and cerebral tissue oxygenation were monitored with near infrared  spectroscopy (NIRS); 5) ventilatory measures; and 6) isocapnic and hypoxic stimuli was assessed by end-tidal carbon dioxide (PetC02) and SaC>2, respectively. RESULTS: Total MSNA, burst frequency  and burst amplitude increased during hypoxia (p<0.01). Post IH, burst frequency  was higher (p<0.01), total MSNA trended towards higher values (p=0.06), there was no effect  on burst amplitude (p=0.82), and the HVR increased significantly from  0.30 ± 0.03 to 0.61 ± 0.12 L min"1 %Sa02"' (means ± SE, p<0.01). Those subjects with the greatest rise in burst frequency  during the hypoxic exposure demonstrated the greatest increase in HVR post IH (r = 0.91, p<0.05); this relationship did not exist pre IH (r = 0.39, p>0.05). During the hypoxic exposure HR, BP, and minute ventilation all increased (p<0.05) and returned to baseline during recovery; however, there was no effect  of  IH. For both the vastus lateralis and cerebral tissue, indices of  tissue oxygenation significantly  decreased (p<0.05) during the hypoxic exposure and returned to baseline values during recovery. Cerebral tissue oxygenation was unaffected  by 10 days of  IH. Vastus lateralis total haemoglobin (tHb) increase from  baseline post IH (p=0.03), where as pre IH values for  tHb did not (. However, tHb values were not statistically different  between trials (p=0.49). There was no difference  between PetC02 or SaCh values in each experimental session (p>0.05). CONCLUSION: Exposure to 10 days of  IH significantly  increases MSNA and augments the ventilatory response to hypoxia. The enhanced MSNA is mediated primarily through an increase in burst frequency,  which shows a strong relationship to HVR post IH. This suggests that concurrent adaptations to the ventilatory and neurovascular control systems may occur with IH. Although our subjects only experienced brief  IH, our data support the hypothesis that repeated exposures to IH in OSA could contribute to the sustained increases in MSNA observed in the absence of  hypoxic stimuli. T A B L E O F C O N T E N T S Abstract ii Table of  Contents iv List of  Tables v List of  Figures vi Acknowledgments vii Introduction 1 Hypothesis 9 Methods 10 Results 19 Discussion 35 Literature Review 71 Appendix A: Representative trace for  one subject 85 Appendix B: Hypoxia and sympathetic drive 86 Appendix C: Sympathetic control via the rostral ventral lateral medulla 87 Appendix D: Hypoxia and renal sympathetics 88 References  89 L I S T O F T A B L E S Table 1. Time line of  study 12 Table 2. Subject characteristics 19 Table 3. Effect  of  IH on normalized values for  MSNA burst frequency  21 Table 4. Effect  of  IH on normalized values for  MSNA burst amplitude 22 Table 5. Effect  of  IH on normalized values for  total MSNA 23 Table 6. Effect  of  IH on percent change in MNSA burst frequency  24 Table 7. Effect  of  IH on percent change in MNSA burst amplitude 25 Table 8. Effect  of  IH on percent change in total MNSA 26 Table 9. Effects  of  IH on ventilatory measures 28 Table 10. Effects  of  IH on cardiovascular measures 33 Table 11. Effects  of  IH on vastus lateralis muscle oxygenation 35 Table 12. Effects  of  IH on cerebral tissue oxygenation 38 L I S T O F F I G U R E S Figure 1. Overview of  the experimental protocol 11 Figure 2. The effect  of  IH on the percent change in muscle sympathetic nervous activity (MSNA) 27 Figure 3. Representative trace for  one subject 79 Figure 4. The effect  of  IH on minute ventilation (Vi) 29 Figure 5. The effect  of  IH on the hypoxic ventilatory response (HRV) 30 Figure 6. The relationship between hypoxic ventilatory response (HVR) and burst frequency  during pre and post IH 31 Figure 7. The effect  of  IH on blood pressure 33 Figure 8. The effect  of  IH on heart rate (HR) 34 Figure 9. The effect  of  IH on the Beer Lambert derived measures of  haemoglobin saturation for  the vastus lateralis muscle 36 Figure 10. The effect  of  IH on the percent change in vastus lateralis muscle tissue oxygenation (mTOI) 37 Figure 11. The effect  of  IH on the Beer Lambert derived measures of  haemoglobin saturation for  the cerebral tissue 39 Figure 12. The effect  of  IH on the percent change in cerebral tissue oxygenation (cTOI) 40 Figure 13. Central pathways involved in hypoxia induced sympathetic activation ... 45 A C K N O W L E D G M E N T S This completion of  this project was made possible by collaboration and exceptional teamwork and therefore,  I must extend my appreciation to numerous people. Thanks to Dr. Bill Sheel for  his guidance over the last two years and for  his confidence  in my ability to complete this project, to Drs. Tim Inglis and Don McKenzie for  their valuable input and advise, and to Dr. Paul Kennedy who took the time to teach me the microneurographic technique. Without the participation of  Dr. Paul Kennedy, this project would not have been possible as he obtained all neural recordings. A special thanks to my "lab mates" for  all their support - especially Dr. Michael Koehle and Glen Foster who were always there to help me out. I am extremely grateful to Stephanie Peters and Jenna Homer for  their assistance in data collection and analysis. Without them I wonder how I would have gotten through the long hours in front  of  the Nitrogen tanks and all the data. The commitment of  all study participants must also be recognized, as they volunteered over twenty hours. Lastly, I would like to thank my family  and friends  for  their support. I N T R O D U C T I O N Understanding the physiological consequences of  hypoxia on the autonomic, cardiovascular, hemodynamic, and ventilatory systems has implications for  many individuals, including: persons with diseases, such as obstructive sleep apnoea (OSA) and congestive heart failure,  those looking to improve athletic performance,  and those ascending to high altitude. Hypoxia can be defined  as a reduction in oxygen availability, either in the inspired air or arterial blood. With exposure to hypoxia biological homeostasis is disturbed. In an effort  to protect vital cellular and physiological system functioning  oxygen sensitive peripheral (94, 127, 129), and when severe enough, central chemoreceptors (137, 150) are activated. Consequently, a brisk increase in ventilation is the initial and most observable physiological response to hypoxia and * functions  to preserve oxygen delivery. Apart from  ventilation, increases in the activity of  the sympathetic nervous system (SNS) activity are evident. Both chemoreceptor (43, 60, 113,114, 153, 159) and baroreceptor (55, 56, 72, 157, 159) activation have been implicated in mediating the sympathoexcitation observed in response to hypoxia. Both these inputs have neural connections with sympathetic control centers in the central nervous system (CNS). Direct measurements of  sympathetic nerve activity can be obtained using a technique called microneurography. In humans microneurography has been used to measure multi unit recordings of  muscle sympathetic nerve activity (MSNA) in peripheral nerves using microelectodes. This technique has proved insightful  for  testing the contribution of  different  stimuli, such as hypoxia on the SNS. Both human and animal models implicate hypoxia, and not changes in carbon dioxide (CO2) or cessation of  breathing as the primary cause of  the enhanced autonomic activity. This statement is supported by evidence of persistent MSNA only after  the removal of  a hypoxic stimulus. Morgan et al. (103) were the first to demonstrate this using a 20 minute exposure to either sustained hypoxia or hyperoxia in a background of  hypercapnia. Both experimental conditions caused an increase in MSNA and ventilation. During recovery, increased MSNA only persisted in the hypoxic trial, when ventilation and chemical stimuli had normalized. What could cause the persistent MSNA after  the removal of  the hypoxic stimulus? Animal and human studies present conflicting  results with regards to the ventilatory and sympathetic responses to hypoxia. This can be attributed to either species-specific  differences  or limitations due to the non-invasive nature of  human work. In rodents, long term facilitation (LTF) of  the carotid body afferent  activity has been observed and it has been suggested that this is the mechanism mediating the maintained increases in sympathetic activity in humans. This theory is supported by data showing continued afferent  activity from  the carotid sinus nerve t during normoxic recovery. In humans, LTF of  the carotid body is not observed and therefore  it is not a likely explanation for  the persistent MSNA. To support this, the hypoxia induced increases in ventilation return to baseline within minutes into recovery. To address the persistent MSNA in humans, two explanations have been presented. First, the gain in chemoreflex  control of  sympathetic output could be higher than that of  ventilation. Therefore,  during recovery, low levels of  afferent  activity from  the carotid body may cause large increases in sympathetic outflow  with no effect  on ventilation. In other words, sensitization of  the carotid body may occur where chemoreceptor drive may continue despite a normalization of  arterial oxygen saturation (SaCh) (121) and may selectively augment sympathetic activity based on central neural structures. Secondly, central regions in charge of  sympathetic activity, such as the medulla may undergo a type of  LTF, analogous to that seen in the carotid bodies of  rodents resulting in maintenance of  neurotransmitter release and/or modulation of  synaptic pathways controlling sympathetic signal transduction. Central LTF could be achieved directly by stimulation of  central chemoreceptor or peripheral chemoreceptor stimulation that leads to centrally mediated increases in sympathetic output. It is well established that local peripheral vasodilatation occurs response to hypoxia and it has been reasoned that this occurs to offset  the sympathetic vasoconstriction. The study of sympathoexcitation and hypoxia has traditionally assumed that stimulation of  the carotid body occurs first,  causing an increase in sympathetic activity and that vasodilatation is a secondary V response initiated with the purpose of  maintaining vascular tone. An alternative view has been postulated, where peripheral vasodilatation is initiated first,  causing a reduction in blood pressure and consequently unloading pressure sensitive baroreceptors (156, 157). In an effort  to maintain blood pressure, baroreceptors will decrease sensory afferent  output which will lead to a cascade of  central neural events that will increase sympathetic activity. In the context of  this hypothesis, the persistent increases in MSNA during normoxic recovery could be explained by a persistent production of  vasodilatory elements causing reductions in blood pressure and therefore  leading to baroreceptor disengagement. The mechanisms controlling sympathetic outflow  are not clear - and strong evidence supporting baroreflex  or chemoreflex  processes have been presented. Regardless, it is not likely that one step along the oxygen sensing pathway is exclusively responsible for  the initial rise in sympathetic activity or its persistence. Indirect measurements of  sympathetic activity with exposure to hypoxia have been made » in humans, but due to the nature of  indirect techniques, results have been equivocal. Few investigations have looked at the long term effects  of  hypoxia on MSNA in humans. Individuals with OSA, a pathological model of  chronic intermittent hypoxia (IH) has been useful  in understanding the potential physiological effects  of  long term repeated nocturnal exposures to hypoxia. These individuals show marked increases in MSNA during normoxia (106, 108) and hypoxia (107). The continuous bouts of  hypoxia have been implicated as the primary cause of  * the elevated MSNA (68), although other conditions intrinsic to this disease my also contribute (106, 108). When treated for  the repeated nocturnal exposures to hypoxia, MSNA is reduced in OSA patients. In healthy humans, Hansen and Sander (57) showed that after  chronic sustained hypoxia (4 weeks at 5360 m), MSNA was higher compared to that at sea level. The elevated MSNA persisted despite either disengagement of  the carotid body via the administration of supplemental oxygen while at altitude or with normoxic breathing with the return to sea level. The persistent MSNA with administration of  supplemental oxygen and the return to sea level could be due to a type of  LTF of  central mechanisms. With long term exposure to hypoxia increases in the ventilatory sensitivity to hypoxia are observed. Peripheral chemoreceptors, specifically  the carotid bodies, are essential in detecting systemic hypoxia and are required for  the hypoxic ventilatory response (HVR) (43, 60, 127, 128). These cells are neuronal in nature and send sensory afferent  signals to the CNS, where they are processed by the respiratory control centers (53). The ventilatory response to hypoxia is dependent on the carotid body as bilateral carotid body resection completely eliminates ventilatory response to hypoxia (60-62). The HVR has been shown to be dependent on the pattern in which hypoxia is administered in animals (131, 133) but not in humans (44). For example, in rodents (121) chronic IH and not chronic sustained hypoxia enhances hypoxic ventilatory sensitivity. Typically, any form  of  hypoxia delivered over the long term increases HVR in humans. At altitude (12 days at 3810 m), Sato et al. (143) showed chronic sustained ^ hypoxia increased the HVR by approximately 50%. With exposure to IH in a laboratory setting Garcia et al. (49) showed that the maximal increases in the HVR were similar when humans were exposed to IH and chronic hypoxia; however, the time course of  the increase in HVR was earlier with IH. Based on these data, it appears that IH can have an enhanced effect  in the ventilatory response compared to other paradigms of  long term hypoxic exposure. The enhanced HVR with IH can be attributed to the unique modulation of  protein and ion pathways occurring within the - carotid body (133), but is not exempt from  alterations in the CNS and efferent  signal transduction. The cardiovascular system is also altered with acute hypoxia and this is in part mediated by the SNS. Cardiovascular alterations function  to increase cardiac output, redistribute blood flow  to essential regions, and counteract hypoxia induced peripheral vasodilatation. In humans, 20 minutes of  acute hypoxia results in increases in heart rate and blood pressure with both variables returning to normal values upon resumption of  normal room air breathing (20, 103, 157, 171, 172). Like the ventilatory response to hypoxia, the heart rate and blood pressure response is dependent on intact carotid bodies (61). With long term exposure to hypoxia in healthy humans, heart rate and blood pressure is unaltered during normoxia (57, 70, 71); however, the sensitivity of  these cardiovascular measures to hypoxia is increased (44, 70). Sympathetically mediated vasoconstriction has been suggested to play an important role in the increased blood pressure response to hypoxia (54, 157). However, it can be reasoned that with the enhanced production of  peripheral vasodilators thereby offsetting  vasoconstriction, it is possible to observe no changes in blood pressure (157). In patients with OSA, high blood pressure is observed during non-apnoeic periods and is attributed to sympathoexcitation caused by long term IH (108, 168). Furthermore, compared to healthy controls, patients with OSA show increased blood pressure sensitivity to hypoxia (106, 107). In an experimental animal set up modeled to simulate some of  the conditions of  OSA, Fletcher and colleagues (41) showed that chronic IH caused a 13.7 torr increase in mean arterial pressure (MAP). In subsequent studies, by the same group also showed that the rise in MAP was dependent on intact carotid bodies (82) and was terminated with chemical sympathectomy (40) suggesting the important role of  the peripheral chemoreceptors and the SNS in the blood pressure response to chronic hypoxia (5). The skeletal muscle haemodynamic response to acute hypoxia is determined by the balance between vasoconstriction and vasodilatation, mediated by sympathetic activation and production of  local dilatory elements, respectively. Human studies have examined hypoxic induced vasodilatation by indirect means. In humans exposed to acute hypoxia (Sa02 = 74%) Leuenberger et al. (83) measured skin and forearm  blood flow  and vascular resistance via plethysmography and showed that skin measurements did not change while there was a significant  rise in forearm  measurements. It was concluded that if  vasodilatation occurs with hypoxia, it must be manifested  locally within the vasculature of  skeletal muscle. In a separate study by the same group femoral  blood flow  velocity acquired using Doppler ultrasound was significantly  decreased during apnoeas coupled with hypoxia versus hyperoxia or normoxia (85, 157, 170). The authors suggested that sympathetic vasoconstriction induced by hypoxia caused the reduction in blood flow.  In line with these results, reductions in forearm  vascular resistance were observed in skeletal muscle during hypoxia when unmasked by local alpha-adrenergic blockade, thereby blunting the sympathetic mediated vasoconstriction and permitting vasodilatation. Tissue oxygenation can be assessed using near infrared  spectroscopy (NIRS), another indirect technique that is useful  in examining the haemodynamic responses to hypoxia (135, 142) and will be determined by blood flow  and tissue metabolism. Using the NIRS technique, the total haemoglobin (tHb) can be calculated as the sum of  the deoxygenated haemoglobin (HHb) and oxygenated haemoglobin (Hb02) signal and represents blood volume, which is a surrogate measurement for  blood flow.  Based on the skeletal muscle vascular responses obtained from blood flow  and vascular resistance measurements during acute hypoxia, one might expect that skeletal muscle tissue oxygenation would be compromised during acute hypoxia. However, this is not the case in animal preparations. In rabbit hind limb muscles exposed to graded hypoxia large increases in HHb with small relative decreases in Hb02 were observed resulting in increases in tHb (142). Long term exposure to hypoxia will have additional affects  on skeletal muscle tissue oxygenation as dilatory and constriction functions  in the vessel can be altered. After  chronic exposure to IH in rats, isolated vessel preparations show dilatory sensitivity to adenosine is increased and vasoconstrictor response to norepinephrine is reduced (122). Others suggest that chronic exposure IH blunts vessel dilatorily responsiveness to hypoxia by reducing nitric oxide release from  the endothelium of  skeletal muscle (15). No investigation has looked at the effect  of  IH on skeletal muscle oxygenation in humans. Like the skeletal muscle, cerebral haemodynamics are affected  by acute hypoxia. Additional factors  must be considered when examining the cerebral haemodynamic response to hypoxia. Cerebral blood flow  is tightly regulated by a phenomenon known as autoregulation which functions  to protect the brain from  high perfusion  pressures through the cerebral vessels. Cerebral blood flow  is increased from  baseline values with exposure to acute hypoxia and this response is highly dependent on CO2 tension (3, 78, 124). After  long term IH, the sensitivity of cerebral blood flow  to hypoxia is reported to increase (77). Alternatively, the sensitivity of  * cerebral oxygenation to hypoxia was reduced which was interpreted as an impairment of  the cerebral vessels to regulate cerebral blood flow  and therefore  tissue oxygenation (44). Direct evidence from  rodent models extends this hypothesis. During acute systemic hypoxia adenosine from  endothelial cells produce the major part of  the hypoxia-induced dilatation in the cerebral tissue (16). These processes may be compromised with long term hypoxia as Philips et al. (122) showed that in isolated cerebral vessel preparations a reduced vasodilatory response to hypoxia ' was evident after  long term IH. Implications of  reduced vasodilatory response can be seen in humans. Patients with OSA show reductions in cerebral oxygenation during periods of  hypoxia (58, 160). Instead of  a reduced vasodilatory response, reductions in cerebral oxygenation with hypoxia might be the due to a decrease in the metabolic activity of  the CNS neurons (109, 113). Additionally, with long term and/or severe hypoxia, neuronal injury, neuron cell death (173), and brain atrophy (46) have been reported and may lead to decrements in cognitive function  (46). Conversely, the metabolic activity of  medullary regions may actually increase during hypoxia, such as the pre-Boetzinger region in charge of  respiratory control, or the rostral ventral lateral medulla (RVLM) in charge of  sympathetic tone (53). The study of  hypoxia on cellular and physiological responses has used a wide range of paradigms and techniques, making comparison among investigations difficult.  Both acute and chronic models have been employed, which have varied in severity (assessed either by the fraction  of  inspired oxygen or as the percentage of  arterial oxygen saturation), pattern (sustained * or intermittent), and exposure duration (minutes, hours, days). Additionally, hypoxia has been examined in combination with differing  levels of  other stimuli, namely carbon dioxide (CO2), atmospheric pressure, and breathing pattern. For our purposes, hypoxia was defined  as an arterial oxygen saturation (SaC>2) of  80%. To minimize the contribution of  other stimuli, end tidal carbon dioxide (CO2) was held at eucapnic levels and spontaneous breathing was permitted. This current protocol was chosen as similar conditions have been used by others (20, 103, 157, * 171, 172) making comparisons between studies possible. Intermittent hypoxia was defined  as 1 hour daily exposures of  hypoxia where Sa02 = -80%. The present study was undertaken to address the effects  of  IH on direct measurements of SNA in humans. Specifically,  we sought to characterize the increases in MSNA during an acute exposure to hypoxia and how this response is modulated after  10 days of  IH. Furthermore, we wanted to test the effects  of  IH on the persistent MNSA during the normoxic recovery period. Concurrent ventilatory, cardiovascular, vastus lateralis oxygenation and cerebral tissue oxygenation measurements were acquired to examine how their response is altered with IH. H Y P O T H E S E S The goal of  the current study was to document the augmentation of  sympathoexcitation, measured as MSNA following  10 days of  IH in healthy males. The primary aim of  the present study was to test the hypothesis that 10 days of  IH would augment the rise in MSNA during an acute 20 minute isocapnic hypoxic exposure. Furthermore, IH was expected to elevate the persistent MSNA during the normoxic recovery period. A secondary purpose was to examine the effect  of  10 days of  IH on the ventilatory, cardiovascular, vastus lateralis oxygenation, and cerebral tissue oxygenation parameters. Lastly, we further  hypothesized that the changes in the hypoxic ventilatory response after  IH would show a strong relationship with the changes in MSNA since both the ventilatory and sympathetic systems have overlapping neural structures in > the CNS and therefore  may undergo concurrent modulation with IH. M E T H O D S All methods and procedures were approved by the Clinical Research Ethics Board at the University of  British Columbia. All data was collected at the Health and Integrative Physiology Laboratory on the University of  British Columbia campus. SUBJECTS Eleven healthy male subjects gave their informed  written consent to participate in the present study. Of  the eleven subjects, MSNA was obtained from  six subjects. Inclusion criteria were as follows:  recreationally active males, between the ages of  19-35, and a body mass index (BMI) of  -24 kg m . The rationale for  these inclusion criteria is based on evidence that sympathetic activity is influenced  by gender, training status, age, and BMI (67, 98). Subjects were excluded if  they had ascended to altitude (>3,000 m) three months prior to testing, had history of  smoking, were taking regular medication, or had been diagnosed with sleep apnoea, asthma, or neurological disease. No subjects had participated in competitive swimming, breath-hold diving, or any other form  of  apnoeic training activity (31). Subjects were asked to refrain  from  caffeine,  alcohol, and exercise for  24 hr prior to all testing procedures. EXPERIMENTAL PROCEDURES Refer  to Table 1 for  a summary of  the experimental time line. See Figure 1 for  a diagram of  the experimental protocol. FAMILIARIZATION: On DAY 1 subjects signed consent forms  and anthropometric data was recorded and pulmonary function  testing was conducted. Additionally, a HVR was performed  to familiarize  subjects with masked and hypoxic breathing. During baseline subjects breathed room air for  10 minutes. The HVR lasted approximately 5 to 7 minutes. The hypoxic exposure was 20 minutes in duration where the Sa02 was reduced to 80% and held constant. Recovery was 20 minutes where subjects were returned to room air breathing. Abbreviations: hypoxic ventilatory response (HVR) PRE INTERMITTENT HYPOXIA (PRE IH): On DAY 2, a four-phased  experimental protocol was conducted, consisting of  a 10 minute baseline, a -5-7 minute HVR, 20 minute isocapnic hypoxic exposure, and a 20 minute normoxic recovery period (see MEASUREMENTS section for  details about each phase). Ventilatory, cardiovascular, oximetry, MSNA, and NIRS measurements were1 collected. Subjects from  which MNSA data was collected were studied in the semi-recumbent position, while the other subjects were studied in the supine position. INTERMITTENT HYPOXIA (IH): Subjects returned to the laboratory daily for  10 consecutive days (DAYS 3-13). Isocapnic-hypoxia was administered, such that Sa02 was maintained at - 8 0 % . On these days only, ventilatory measurements were recorded and subjects were allowed to sit upright to read, watch videos, and listen to music. POST INTERMITTENT HYPOXIA (POST IH): On DAY 14 the identical experimental protocol was conducted and the same measurements were recorded as on DAY 2. Table 1: Time line of  study DAY 1 EXPERIMENTAL DAY 2 TRAINING DAY 3 - 1 3 EXPERIMENTAL DAY 14 FAMILIARIZATION P R E I H INTERMITTENT HYPOXIA POSTIH DESCRIPTION Consent Forms 4 Experimental Protocol Daily Hypoxia • Experimental Protocol Pulmonary Function Testing and Anthropometrics Data 4 I Baseline HVR Hypoxic Exposure Exposures 1-10 I Baseline HVR Hypoxic Exposure Familiarization with Mask and HVR procedure Recovery Re overy MEASUREMENTS Height, weight, age, BMI, FVC, FEVb FEVi/FVC, HVR, VENT HVR, VENT, HR, BP, Sa02j MSNA, NIRS VENT, Sa02 HVR, VENT, HR, BP, Sa02 MSNA, NIRS The days included in the study are indicated along the horizontal bars and the descriptions and measurements taken each day are indicated along the vertical bars. Abbreviations: body mass index (BMI), forced  vital capacity (FVC), forced  expiratory volume in one second (FEV|), forced  expiratory volume in one second as a percentage of  predicted (FEVJ/FVC), hypoxic ventilatory response (HVR), ventilatory measurements (VENT), arterial oxygen saturation (Sa02), heart rate (HR) blood pressure (BP), muscle sympathetic nerve activity (MSNA), near infrared  spectroscopy (NIRS) MEASUREMENTS All variables were acquired online, in real time using an analog-to-digital converter (Powerlab/16SP ML795 ADInstruments, Colorado Springs, CO, USA) interfaced  with a personal computer (Satellite, Toshiba, Irvine, CA, USA). All variables were sampled at 1kHz. Data were stored on a personal computer for  offline  analysis using commercially available software  (Chart 5 for  Powerlab, ADInstruments, Colorado Springs, CO, USA). ANTHROPOMETRIC MEASURES: Height, weight, BMI , and age were documented. PULMONARY FUNCTION TESTING: Using a calibrated spirometer (Spirolab II, Medical International Research, Via del Maggiolino, Roma, Italy) and abiding by the recommendations of the American Thoracic Society, pulmonary function  was assessed. Three forced  vital capacity (FVC) manoeuvers were performed  and FVC, forced  expiratory volume in one second (FEVi), and forced  expiratory volume in one second as a percentage of  FVC (FEVi/FVC) were documented. Those subjects unable to achieve 80% of  their predicted capacity as determined by the European Respiratory Society prediction equations for  adult men were excluded from  the study (1). VENTILATORY MEASUREMENTS: Inspiratory flow  was obtained using a heated pneumotach connected to the inspired side of  a face  mask (8930 Series, Hans Rudolph Inc., Kansas City, MO, USA). Prior to each test, flow  calibration was carried out with a 3 L syringe (MedTech, Model #2030-2, Hans Rudolph Inc, Kansas City, MO, USA). Using the integral of  the inspiratory flow signal, inspiratory volume of  each breath was determined. During offline  analysis, tidal volume (VT; L) and breathing frequency  (f B; breaths min"1) values were calculated from  inspiratory volume and minute ventilation (VI; L min"1) was calculated as the product of  fa  and VT. Dedicated analyzers were used to monitor end-tidal oxygen (Pet02) and carbon dioxide (PetC02) (S-3A/I and CD-3A, Applied Electrochemistry, Pittsburg, PA, USA). Analyzers were calibrated prior to each test using medical grade gases of  known concentrations. HYPOXIC VENTILATORY RESPONSE (HVR): The H V R procedure was conducted in a similar manner to that described previously (14) and used in our laboratory (44, 52, 75). Subjects breathed room air from  a mixing chamber (13.5 L) as 100% nitrogen (N2) was progressively added to the inspiratory circuit (-2 L every 30 seconds), thereby reducing the concentration of oxygen until SaC>2 reached 80%. Isocapnia was maintained during the procedure by monitoring end tidal CO2 (PetC02) and adding 100% C02 , as required, to the inspired tubing via a needle inserted -30 cm from  the mouth piece. The total time for  each HVR procedure was - 5-7 minutes. The HVR was calculated using a linear regression model for  V\  versus Sa02. The slope represents the HVR, or the ventilatory sensitivity to hypoxemia. Values are expressed as L min"1 %Sa02"1. ISOCAPNIC HYPOXIC EXPOSURE: Immediately following  the H V R procedure, subjects continued to breathe a hypoxic inspirate from  the mixing chamber for  20 minutes, such that the SaC>2 was i maintained at a mean of  80% and isocapnia was maintained. These procedures are similar to those used by others (20, 103, 171, 172). NORMOXIC RECOVERY: Following the 20 minute hypoxic exposure, the flow  of  N2 ceased and subjects were returned to room air breathing for  20 minute. The PetC02 trace was continually monitored and CO2 was regulated at baseline values if  needed. MICRONEUROGRAPHY. Direct intraneural recordings of  multiunit post ganglionic MSNA were acquired using a common microneurographic technique that has been employed previously by others (19, 20, 103, 156, 161, 171, 172). Recordings were made from  the peroneal nerve. An appreciation for  the location of  the nerve was obtained through surface  stimulation (Stimulator, model S48, Astromed Inc, Grass Product Group, W.Warwick, RI, USA). Upon location, two sterile microelectrodes (tip diameter 5-10 |im, 30-35 mm long, Fredrick Haer, Bowdoinham, ME) were inserted. Stimulating pulses were administered via the reference  microelectrode (UNR32FRS) and once a clean dorsiflexion  movement was evoked using a low stimulating voltage (-5-10 Hz), the active tungsten microelectrode (UNA32F2S) was inserted for  recording of  MSNA. Nerve signals were amplified  (custom-built microneurography preamplifier  and amplifier,  Yale University, New Haven, CT, USA) with a total gain of  10,000. Processed signals were band pass filtered  (700-2000 Hz), rectified  and discriminated. The nerve signal was integrated at a time constant of  100 ms (Integrator model B937C, Bioengineering, University of Iowa, Iowa City, IA, USA). The nerve signal was assessed via audio representation of  burst activity (Audio Monitor, model AMIO, Astromed Inc, Grass Product Group, W. Warwick, RI, USA) and visual inspection of  the mean voltage neurogram (ADInstruments, Colorado Springs, CO, USA). The following  criteria were used to validate the recording site: 1) demonstration of pulse synchronous bursts occurring 1.2-1.4 sec after  a QRS complex (89, 92, 167); 2) reproducible activation upon apnoea or phase II and III of  a Valsalva manoeuvre; 3) no activation upon pinch, stroking of  the skin, or startle stimuli (indicating skin sympathetic activation); and 4) a signal to noise ratio of  >3:1(161). The integrated neurogram was high pass filtered  at 0.5 Hz to set the mean baseline to zero and low pass filtered  at 10 Hz to smooth the signal for  analysis. The integrated and filtered 4 neurogram was then time shifted  to align each burst with the preceding R-wave. Burst labelling was automated and then manually inspected and edited according to the validation criteria described above and yielded burst frequency  (burst min"1) values. To normalize the neurogram, commercially available software  (Chart 5, ADInstruments, Colorado Springs, CO, USA) was used to establish baseline and threshold settings for  each individual data file  and permitted calculation of  peak amplitude (arbitrary units). Total MSNA (arbitrary units) was calculated as » the product of  burst frequency  and peak amplitude. CARDIOVASCULAR MEASUREMENTS: Electrocardiogram (ECG; ADInstruments, ML110, 5303) tracing was continuously collected from  a standard bipolar limb lead. Heart rate (HR) was determined via the peak detection of  the R-wave. Beat-by-beat blood pressure was obtained using non-invasive photoplethysmography at the finger  (Finometer, Finapres Medical System, Arnhem, Netherlands). To ensure accurate estimates of  blood pressure, the hydrostatic height sensor was zeroed prior to each test and subject height, weight, and age were entered into the device. Similar methods have been validated as reliable measures of  blood pressure (63, 64). Additional blood pressure measurements were acquired from  an automated cuff  (BPM-100, VSM Medical Technologies Ltd, Vancouver, Canada) every two minutes throughout the experimental protocol and statistical analyses were preformed  on these values. The on-line blood pressure trace was calibrated from  the cuff  measurements collected during baseline. The maximum and minimum values of  the beat-by-beat blood pressure trace were determined and represented systolic (SBP) and diastolic (DBP) blood pressure, respectively. Mean arterial blood pressure (MAP) was calculated as the sum of  DBP and 1/3 (SBP-DBP). PULSE OXIMETERY: Finger oximetery was used to monitor SaC>2 (3740, Ohmeda, Louisville, CO, USA). This is a non-invasive tool to determine the delivery of  oxygen using an absorbtion spectrum from  a two-wavelength pulsatile system. Calculations are made based on the relative percentages of  Hb02 and HHb chromophores and values are displayed as Sa02 (%). NEAR-INFRARED SPECTROSCOPY (NIRS). Oxyhaemoglobin (Hb02; (iMol), deoxyhaemoglobin (HHb; (iMol) and tissue oxygenation index (TOI; %) were assessed in the right vastus lateralis muscle and right cerebral cortex using the N I R O - 3 0 0 (Hamamatsu Photonics K.K., Hamamatsu, Japan). Total haemoglobin (tHb) was calculated as the sum of  Hb02 and HHb. The NIRO-3QO uses four  wavelengths (775, 810, 847, and 913nm) and employs two theoretical models: spatially resolved spectroscopy to calculate TOI and the modified  Beer-Lambert Law to assess the oxygenation status of  the haemoglobin molecule. The details of  these models are described elsewhere (23, 24, 87, 97). For both the brain and muscle, a tissue specific  differential pathlength factor  (DPF) was multiplied by probe spacing (4.0 -5.0 cm) and was internally set -<, within the NIRO-300 unit. The optodes, containing a light source and detector were placed in a black vinyl holder that shields light and were fixed  against the skin with double sided tape and loosely covered with a dark cloth. One optode was applied to the right side of  the head with detection probe was placed closest to the midline of  the frontal  lobe at the level of  the hairline. Care was taken to avoid placement over the temporal muscles and sinuses. These methods are in compliance with those used previously (44, 74, 115). For the brain, a DPF of  5.93 was used (87, 164); therefore the pathlength set within the NIRO unit was 23.7 - 29.7 cm. A separate optode was applied to the right vastus lateralis muscle in accordance with criteria used in other investigations (21, 22). The detector was placed proximally, midway between the greater trochanter and the lateral condyle of  the knee. Care was taken to avoid placement over the dense fascia  of  the IT band. For skeletal muscle, the DPF used was 4.0 (23, 28); therefore  the pathlength set within the NIRO unit was 16.0 - 20.0 cm. DATA AND STATISTICAL ANALYSIS. Ventilatory, cardiovascular, and NIRS data were averaged over 5 minute sections during baseline, hypoxic exposure, and recovery and are expressed as absolute values. Additionally, these measurements are expressed as changes from  baseline and . for  each 5 minute period during the hypoxic exposure and recovery period. MSNA is reported as absolute normalized units and as percent change from  baseline for  within subject comparison (pre and post IH). Statistical analysis was performed  on both absolute values and percent change values, however emphasis was placed on the percent change in MSNA only. The rationale for MSNA data to be presented in this manner is three-fold:  1) MSNA is not reported as absolute values as it is dependent on the proximity of  the microelectrode to the nerve (161); 2) MSNA is highly variable between subjects (19, 98, 161); and 3) to allow for  comparison between f previously conducted investigations. All variables are expressed as means ± SE. Statistical analyses were performed  at a significance  level of  a = 0.05 using commercially available software  (Statistica software  V.6.1, Statsoft  Inc, Tulsa, OK, USA). For each variable a repeated measures ANOVA was performed to 1) determine the difference  between baseline, the isocapnic-hypoxic exposure, and the recovery; and 2) the differences  between pre and post IH values. When a significant  F-ratio was * detected, Tukey's test was applied poc-hoc to ascertain where the differences  resided. Linear correlation analysis was used to examine the relationship between HVR and maximum burst frequency  for  both pre and post IH. A paired t-test was preformed  to analyze the difference between pre and post IH values of  HVR. R E S U L T S SUBJECT CHARACTERISTICS. All subjects completed each of  the 14 days of  the study. Cardiovascular, ventilatory, and NIRS measurements were acquired from  all subjects (n=l 1). MSNA measurements were obtained from  only six subjects. Mean descriptive data for anthropometric and pulmonary function  testing can be found  in Table 2 and were collected on the Familiarization day (Day 1). The pulmonary function  values for  each subject are the mean of three manoeuvers. Table 2. Subject characteristics ANTHROPOMETRIC DATA PULMONARY FUNCTION DATA Subject Age Height Mass BMI FVC F E V ! FEV^VC Number (yrs) (M) (kg) (kg-m2) (L) (L) (%) 1* 20 1.71 72 24.6 4.9 4.2 85.2 2* 33 1.78 79 24.9 5.2 4.4 85.3 3* 27 1.85 70 20.5 6.2 4.8 85.6 4* 27 1.84 77 22.7 6.1 4.6 86.1 5* 23 1.89 94 26.2 5.4 4.7 86.5 6* 24 1.85 89 26.0 6.0 4.7 77.5 7 25 1.87 75 21.5 6.6 5.3 80.5 8 24 1.91 106 29.1 5.3 4.5 83.6 9 21 1.86 81 23.4 6.2 4.9 82.1 10 26 1.92 109 29.6 6.0 5.2 86.0 11 24 1.80 86 26.5 6.2 5.4 87.2 Mean 24.9 1.8 85.3 25.0 5.8 4.8 84.1 (±SE) (1.0) (0.02) (4.0) (0.87) (0.16) (0.11) (0.90) Individual data was collected on the Familiarization day (Day 1). Pulmonary function  data is reported as the mean of  three FVC manoeuvres for  each subject. Values are expressed as means (±SE). Cardiovascular, ventilatory, and NIRS measurements were acquired from  all subjects (n=l 1). MSNA measurements were obtained from  only six subjects and are indicated (*). Abbreviations: body mass index (BMI), forced  vital capacity (FVC), forced  expiratory volume in one second (FEV[), forced  expiratory volume in one second as a percentage of  predicted (FEV,/FVC), muscle sympathetic nervous activity (MSNA). EFFECTS OF IH ON MSNA. Individual and mean data for  absolute (normalized) burst frequency, amplitude, and total MNSA can be found  in Tables 3, 4, and 5 respectively. Individual and mean data for  percent change in burst frequency,  amplitude, and total MNSA can be found  in Tables 6, 7, and 8 respectively. Figure 2 displays the percent change in burst frequency  (A), amplitude (B), and total MNSA (C). A mean value for  baseline and for  each 5 minute period during the hypoxic exposure and recovery period was calculated. Burst frequency  increased from  baseline immediately with exposure to hypoxia and remained significantly  elevated for  the duration of  the exposure and recovery period (p<0.001). Burst frequency  was significantly  higher post IH compared to pre IH during the hypoxic exposure and recovery (p=0.01). Burst amplitude increased from  baseline immediately with exposure to hypoxia and remained significantly elevated for  the duration of  the exposure and recovery period (p<0.01); however, there was no difference  between pre and post IH burst amplitude (p=0.82). For both pre and post IH, total MSNA increased significantly  during the hypoxic exposure (p<0.001) mediated primarily by the increases in burst frequency.  Post IH, total MSNA values trended to be higher than pre IH values (p=0.06). Figure 3 is a representative trace of  MSNA and corresponding cardiovascular and ventilatory variables and can be found  in Appendix A. These data represent 30 seconds of baseline, hypoxia exposure, and recovery collected during the post IH trial from  subject 5. Although ventilatory, cardiovascular, and SaC>2 all return to baseline values during recovery, an appreciation of  a persistence in the MSNA can be acquired from  the mean voltage neurogram. BASELINE HYPOXIC EXPOSURE RECOVERY 5 10 15 min 20 min 25 min 30 min 35 min 40 min 45 min 50 min min min PRE IH Subject 1 21.6 19.9 21.9 21.8 22.2 20.5 21.1 19.1 20.0 21.3 2 20.7 18.7 24.3 26.0 24.0 27.5 28.2 30.5 30.1 27.3 3 16.4 16.7 19.2 17.4 18.0 19.1 16.9 20.5 16.0 16.4 4 15.1 13.2 16.4 16.6 16.3 16.3 15.5 16.3 14.2 14.4 5 8.6 9.7 11.7 12.3 11.1 13.5 14.0 10.1 11.9 12.1 6 22.8 21.8 24.1 26.5 25.8 26.6 27.4 24.7 24.2 25.3 Mean 17.5 16.7 19.6 20.1 19.6 20.6 20.5 20.2 19.4 19.5 (±SE) (2.2) (1.8) (2.0)*+ (2.3)*+ (2.3)*+ (2.3)*+ (2.5)*+ (2.9)*+ (2.8)*+ (2.5)*+ POSTIH Subject 1 8.6 6.2 11.0 12.4 12.0 13.4 12.3 10.5 9.5 9.4 2 19.0 19.0 23.6 24.4 26.8 27.8 28.6 28.2 27.8 28.6 3 17.7 16.0 25.0 20.8 22.4 24.4 24.6 23.8 26.2 26.0 4 11.5 10.4 18.5 19.5 25.5 27.5 21.3 25.5 22.8 20.5 5 14.0 7.8 12.0 16.2 13.0 13.2 14.2 16.3 12.7 11.6 6 15.4 15.2 19.4 25.8 26.2 25.8 29.8 24.6 25.8 26.8 Mean 14.4 12.4 18.3 19.9 21.0 22.0 21.8 21.5 20.8 20.5 (±SE) (1.6) (2.1) (2.4)*+ (2.1)*+ (2.8)*+ (2.8)*+ (3.0)*+ (2.7)*+ (3.2)*+ (3.4)*+ The MSNA trace was high pass filtered  at 10 Hz for  normalization purposes, setting the mean voltage to zero. Burst frequency  values are reported as absolute bursts per minute for  each 5 min period during baseline, the hypoxic exposure, and recovery (n=6). Values are expressed as means (±SE). Significance  was set at p<0.05 and is indicated as change from  baseline (*) and difference  between pre and post IH (+) Abbreviations: intermittent hypoxia (IH), muscle sympathetic nerve activity (MSNA) f BASELINE HYPOXIC EXPOSURE RECOVERY 5 min 10 min 15 min 20 min 25 min 30 min 35 min 40 min 45 min 50 min PREIH Subject 1 18.4 17.5 22.8 21.0 21.0 22.6 25.2 25.8 27.0 23.6 2 17.6 18.4 21.4 21.0 20.8 25.0 23.8 23.4 23.4 23.4 3 16.4 16.7 19.2 17.4 18.0 19.1 16.9 20.5 16.0 16.4 4 12.0 13.6 19.4 23.8 22.6 24.9 18.2 25.8 21.2 22.0 5 15.4 20.0 20.8 18.2 21.7 19.4 20.6 18.5 17.9 19.7 6 20.2 23.2 29.0 24.2 26.4 27.2 25.8 28.4 28.0 29.0 Mean 16.7 18.2 22.1 20.9 21.8 23.0 21.8 23.7 22.2 22.3 (±SE) (1.2) (1.3) (1.5)* (1.1)* (1.1)* (1.3)* (1.5)* (1.5)* (2.0)* (1.7)* POSTIH Subject 1 8.6 6.2 11.0 12.4 12.0 13.4 12.3 10.5 9.5 9.4 2 19.0 19.0 23.6 24.4 26.8 27.8 28.6 28.2 27.8 28.6 3 17.7 16.0 25.0 20.8 22.4 24.4 24.6 23.8 26.2 26.0 4 11.5 10.4 18.5 19.5 25.5 27.5 21.3 25.5 22.8 20.5 5 14.0 7.8 12.0 16.2 13.0 13.2 14.2 16.3 12.7 11.6 6 15.4 15.2 19.4 25.8 26.2 25.8 29.8 24.6 25.8 26.8 Mean 14.4 12.4 18.3 19.9 21.0 22.0 21.8 21.5 20.8 20.5 (±SE) (1.6) (2.1) (2.4)* (2.1)* (2.8)* (2.8)* (3.0)* (2.7)* (3.2)* (3.4)* The MSNA trace was high pass filtered  at 10 Hz for  normalization purposes, setting the mean voltage to zero. Burst amplitude values are reported as absolute normalized mVunits for  each 5 min period during baseline, the hypoxic exposure, and recovery (n=6). Values are expressed as means (±SE). Significance  was set at p<0.05 and is indicated as change from  baseline (*) Abbreviations: intermittent hypoxia (IH), muscle sympathetic nerve activity (MSNA) BASELINE HYPOXIC EXPOSURE RECOVERY 5 min 10 min 15 min 20 min 25 min 30 min 35 min 40 45 min 50 min min PRE IH Subject 1 397.8 348.5 498.5 457.1 466.8 463.3 532.9 493.4 540.9 502.9 2 364.0 344.0 519.1 546.0 500.2 688.3 672.3 714.2 704.2 639.1 3 269.5 278.5 369.1 303.4 324.8 365.1 286.8 420.8 255.4 268.8 4 181.6 179.5 317.8 394.6 367.6 404.9 281.7 420.5 302.0 315.9 5 132.4 194.4 243.4 223.6 239.9 262.0 289.1 186.0 213.1 238.7 6 350.7 331.1 621.7 693.9 666.5 793.2 673.4 638.0 649.2 649.0 Mean (±SE) 282.7 (43.9) 279.3 (31.1) 428.3 (58.1)* 436.4 (69.4)* 427.6 (61.7)* 496.1 (83.3)* 456.0 (79.2)* 478.8 (76.3)* 444.1 (87.6)* 435.7 (76.1)* POSTIH Subject 1 105.9 73.2 130.4 156.3 149.5 170.0 151.1 136.3 114.1 139.7 2 290.4 282.5 435.1 448.0 506.9 512.0 462.1 493.6 448.5 476.5 3 236.3 197.1 361.8 330.8 391.2 450.5 443.1 391.2 382.0 415.9 4 137.4 139.7 323.9 322.1 444.9 534.8 362.1 394.1 375.8 338.5 5 196.3 89.3 185.7 283.1 201.2 174.5 189.2 236.0 168.8 155.8 6 580.0 555.4 836.0 1078.8 1005.2 988.8 882.7 797.5 828.2 863.0 Mean (±SE) 257.7 (70.2) 222.9 (73.8) 378.8 (102.8)* 436.5 (134.6)* 449.8 (125.3)* 471.8 (123.3)* 415.1 (107.7)* 408.1 (94.0)* 386.2 (103.8)* 398.2 (108.7)* The MSNA trace was high pass filtered  at 10 Hz for  normalization purposes, setting the mean voltage to zero. Total MSNA values are reported absolute normalized arbitrary units and are the product of  burst frequency  and burst amplitude. Total MSNA values are reported for  each 5 min period during baseline, the hypoxic exposure, and recovery (n=6). Values are expressed as means (±SE). Significance  was set at p<0.05 and is indicated as change from  baseline (*) Abbreviations: intermittent hypoxia (IH), muscle sympathetic nerve activity (MSNA) BASELINE HYPOXIC EXPOSURE RECOVERY 10 min 15 min 20 min 25 min 30 min 35 min 40 min 45 min 50 min PREIH Subject 1 97.5 130.3 120.0 120.0 129.1 144.0 147.4 154.3 134.9 2 97.8 116.3 114.1 113.0 135.9 129.3 127.2 127.2 127.2 3 100.8 115.1 104.4 108.0 114.5 101.5 122.9 95.7 98.2 4 106.3 142.6 175.0 166.2 183.1 133.8 189.7 155.9 161.8 5 113.0 117.5 102.8 122.5 109.3 116.7 104.3 101.1 111.2* 6 106.9 133.6 104.3 113.8 117.2 111.2 122.4 120.7 129.0 Mean 103.7 125.9 120.1 123.9 131.5 122.7 135.7 125.8 127.0 (±SE) (2.5) (4.6)*+ (11.4)*+ (8.7)*+ (11.1)*+ (6.5)*+ (12.2)*+ (10.5)*+ (8.9)*+ POSTIH Subject 1 83.8 177.4 200.6 193.3 216.8 198.6 168.9 152.8 151.6 2 100.0 124.2 128.6 141.1 146.3 150.4 148.4 146.3 150.5 3 95.1 156.3 130.0 140.0 152.5 154.1 148.8 163.8 162.5 4 95.0 178.9 187.7 245.5 265.0 205.8 245.6 219.9 198.1 5 71.6 153.8 207.7 166.7 169.2 182.1 209.0 162.4 149.1 6 99.3 168.6 171.2 168.6 194.8 160.8 168.6 175.2 175.2 Mean 90.8 159.9 171.0 175.9 190.8 175.3 181.6 170.1 164.5 (±SE) (11.1) (20.3)*+ (34.6)*+ (39.5)*+ (45.0)*+ (23.7)*+ (38.4)*+ (26.4)*+ (19.2)*+ Burst frequency  values are reported bursts per minute and are represented as change from  baseline. A mean value for  baseline was calculated and for  each 5 min period during the hypoxic exposure and recovery period (n=6). Values are expressed as means (±SE). Significance  was set at p<0.05 and is indicated as change from  baseline (*) and difference  between pre and post IH (+). Abbreviations: intermittent hypoxia (IH), muscle sympathetic nerve activity (MSNA) BASELINE HYPOXIC EXPOSURE RECOVERY 10 min 15 min 20 min 25 min 30 min 35 min 40 min 45 min 50 min PREIH Subject 1 95.9 109.8 109.3 111.6 103.0 106.2 96.0 100.6 107.0 2 95.0 129.7 139.0 128.6 147.2 151.1 163.2 160.9 146.0 3 100.8 115.1 104.4 108.0 114.5 101.5 122.9 95.7 98.2 4 93.2 124.1 125.6 123.2 123.2 117.2 123.5 107.9 108.8 5 106.1 120.4 126.4 113.8 139.3 144.1 103.7 122.5 124.8 6 97.8 110.6 121.5 118.5 122.1 125.6 113.5 111.2 116.2,, Mean 98.1 118.3 121.1 117.3 124.9 124.3 120.5 116.5 116.9 (±SE) (1.9) (3.2)* (5.2)* (3.2)* (6.6)* (8.2)* (9.7)* (9.7)* (6.9)* POSTIH Subject 1 97.9 100.5 106.5 105.7 107.2 104.0 110.3 102.0 125.9 2 98.6 124.0 123.3 127.2 123.9 108.8 117.7 108.5 112.0 3 95.9 117.5 129.1 141.8 149.9 145.9 133.4 118.3 129.8 4 105.8 129.6 122.8 129.8 144.5 125.9 114.9 122.3 122.3 5 89.9 135.2 152.6 135.1 115.5 116.4 126.4 116.4 117.0 6 98.5 117.9 114.4 116.2 124.3 124.4 116.3 110.9 111.5 Mean 97.8 120.8 124.8 126.0 127.5 120.9 119.8 113.1 119.8 (±SE) (2.1) (4.9)* (6.5)* (5.4)* (6.8)* (6.1)* (3.5)* (3.0)* (3.1)* Burst amplitude values are reported as normalized mVunits and are represented as change from  baseline. A mean value for  baseline was calculated and for  each 5 min period during the hypoxic exposure and recovery period (n=6). { Values are expressed as means (±SE). Significance  was set at p<0.05 and is indicated as change from  baseline (*) Abbreviations: intermittent hypoxia (IH), muscle sympathetic nerve activity (MSNA) B A S E L I N E H Y P O X I C E X P O S U R E R E C O V E R Y 10 min 15 min 20 min 25 min 30 min 35 min 40 min 45 min 50 min PRE IH Subject 1 93.4 143.1 131.2 133.9 132.9 152.9 141.6 155.2 144.3 2 100.0 150.9 158.7 145.4 200.1 195.4 207 .6 204.7 185.8 3 101.7 132.5 108.9 116.6 131.1 103.0 151.1 91.7 96.5 4 99.4 177.0 219.8 204.8 225.6 156.9 234.3 168.3 176.0 5 58.7 73.5 67.5 72.5 79.1 87.3 56.2 64.3 72.1 6 100.0 187.7 209.5 201.3 239.5 203.3 192.7 196.0 196.0 Mean 92.2 144.1 149.3 145.7 168.1 149.8 163.9 146.7 145.1 (±SE) (6.8) (16.6)* (24.1)* (20.8)* (25.9)* (19.3)* (25.9)* (23.3)* (20.8)* POST IH Subject 1 81.7 178.2 213.6 204.3 232.3 206 .6 186.3 155.9 190.9 2 98.6 154.1 158.6 179.5 181.3 163.6 174.7 158.8 168.7 3 91.0 183.5 167.8 198.4 228.5 224.8 198.5 193.7 210.9 4 100.8 231 .9 230.6 318.5 382.9 259 .2 282.1 269 .0 242.3 5 62.6 207 .9 316.9 225.1 195.3 211.8 264.1 189.0 174.3 6 97.8 150.5 194.2 181.0 178.0 158.9 143.6 149.1 155.4 Mean 88.8 184.4 213 .6 217.8 233.1 204.1 208 .2 185.9 190.4 (±SE) (6.0) (12.8)* (23.5)* (21.4)* (31.5)* (15.6)* (22.0)* (18.3)* (13.1)* Total MSNA values are reported normalized arbitrary units and are represented as change from  baseline. A mean value for  baseline was calculated and for  each 5 min period during the hypoxic exposure and recovery period (n=6). Values are expressed as means (±SE). Significance  was set at p<0.05 and is indicated as change from  baseline (*) Abbreviations: intermittent hypoxia (IH), muscle sympathetic nerve activity (MSNA) Figure 2: The effect  of  IH on the percent change in muscle sympathetic nervous activity (MSNA). A mean value for baseline and for  each 5 min period during the hypoxic exposure and recovery was calculated (n=6). Values are expressed as means ± SE and symbolized as pre (o) and post (•) IH. Significance  was set at p<0.05 and is represented as change from  baseline (*) and difference  between pre and post IH (+). The area between the dashed lines indicates the hypoxic exposure. A: Burst frequency  increased significantly  over time (p<0.001), as a function of  protocol (p<0.001), and as a result of  time vs. protocol (p<0.001). B: Amplitude increased significantly  over time (p<0.001); however, protocol and time vs. protocol were not significantly  different  between pre and post IH (p=0.82 and p=0.89, respectively). C: Total MSNA increased significantly  over time (p<0.001), approached significance  as a function  of  protocol (p=0.08), and approached significance  as a result of  time vs. protocol (p=0.06). Note the difference  in scales of  the y-axis. A Time (minutes) B Time (minutes) c Time (minutes) EFFECTS OF IH ON THE VENTILATORY RESPONSE TO HYPOXIA. Table 9 displays the absolute values for  ventilatory measures during the entire period of  baseline and for  each 5 minute period during the hypoxic exposure and recovery. During pre IH, fe  increased during the hypoxic exposure when compare to baseline (p<0.001) and remained elevated for  15 minute into recovery Table 9. Effects  of  IH on ventilatory measures BASELINE HYPOXIC EXPOSURE RECOVERY 10 min 15 min 20 min 25 min 30 min 35 min 40 min 45 min 50 min PREIH f B (breaths min"1) 12.6 14.6 14.9 14.7 15.2 14.6 14.8 14.4 13.5 (1.2) (1.1)* (1.1)* (0.90)* (1.0)* (1.1)* (1.1)* (1.1)* (1.2) VT (litres) 0.81 1.1 0 .99 0.92 0 .92 0 .79 0.75 0.74 0.80 V, (1 min"1) (0 .12) (0.08)* (0.11)* (0.90)* (0.13)* (0 .12) (0-13) (0.09) (0.15) 7.3 10.9 10.6 10.3 9.8 7.4 7.4 7.5 •7.5 (0.98) (1.4)* (1.5)* (1.4)* (1.4)* (1.1) (1.1) (1.2) (1.2) Sa02 (%) 97.3 80.9 80.8 80.5 80.4 94.4 97.4 97.4 97.4 (0 .28) (0.99)* (0.94)* (0.79)* (1.0)* (0.40) (0.22) (0.23) (0.22) Pe tC02 (mmHg) 41 .4 42 .0 41 .2 41.1 41.3 41.5 41 .2 41.3 41.6 (0 .82) (1.1) (1.2) (1.4) (1.2) (0 .80) (0.98) (1.1) (1.3) POSTIH f B (breaths min"1) 12.9 14.2 14.0 13.8 13.2 12.7 12.7 12.6 12.2 (1.0) (1.1) (1.2) (1.1) (1.1) (1.0) (1.1) (0.9) (0.90) VT (litres) 0.75 1.0 1.0 1.0 0 .96 0.71 0 .72 0.75 0.75 V! (1 min"1) (0 .07) (0.06)* (0.07)* (0.07)* (0.07)* (0 .04) (0.03) (0.03) (0.05) 6.4 9.8 9.7 9.3 8.9 6.31 6.4 6.5 6.6 (1.2) (1.7)* (1.8)* (1.7)* (1.6)* (1.1) (1.2) (1.2) (1.2) Sa02 (%) 97.4 79.7 80.5 80.2 79.9 94.6 97.6 97.7 97.7 (0 .14) (0.48)* (0.46)* (0.71)* (0.32)* (0.33) (0.36) (0.26) (0.10) Pe tC02 (mmHg) 41 .2 41.7 41.6 41 .2 41.3 41 .7 40 .9 41 .0 41.4 (0 .93) (1.2) (1.4) (1.5) (1.7) (1.2) (1.2) (1.3) (1.2) Absolute ventilation values were calculated as the mean values for  the entire period of  baseline and for  each 5 min period during the hypoxic exposure and recovery (n=l 1). Values are expressed as means (±SE). Significance  was set at p<0.05 and is indicated as change from  baseline (*). Abbreviations: intermittent hypoxia (IH), respiratory rate (f B), tidal volume (VT), minute ventilation (Vi), arterial oxygen saturation (Sa02), end tidal carbon dioxide (PetC02) (p=0.04), eventually returning to baseline during the last 5 minute of  recovery. Post IH, increases in fe  were observed (p=0.01) and during recovery fa  returned to baseline. For both pre and post IH, VT increased from  baseline and remained significantly  elevated during the hypoxic exposure o (p<0.001), returning to baseline values during recovery. There was no significant  differences  in VT between pre and post IH (p=0.69). Significant  increases in Vi were observed from  baseline during the hypoxic exposure for  both pre and post IH (p<0.001), mediated primarily through f B. During recovery, Vi returned to baseline values. There was no significant  difference  between pre and post IH for  Vi (p=0.78). Figure 4 displays Vi during baseline, the hypoxic exposure, and recovery for  pre and post IH. Figure 4. The effect  of  IH on minute ventilation (V,). A mean value for  baseline and for  each 5 min period during the hypoxic exposure and recovery was calculated (n=l 1). Data is represented in absolute terms and as pre (o) and post (•) IH. The area between the dashed lines indicates the hypoxic exposure. Significance  was set at p<0.05 and is indicated as change from  baseline (*). Values are expressed as means ± SE. Significant  increases in Vi were observed from  baseline during the hypoxic exposure for  both pre and post IH (p<0.001). During recovery, V| returned to baseline values. There was no significant  difference  between pre and post IH for  V| (p=0.78). I —©—PRE-IH —•— POST-IH 1 , 1 10 15 20 25 30 35 40 45 50 T ime (minutes) Mean values for  HVR increased from  0.30 ± 0.07 to 0.61 ± 0.29 L min"1 %Sa02"' (p=0.01), for  pre and post IH, respectively. All subjects showed an increase in HVR with the magnitude of  increases ranging from  0.06 to 0.68 L min' 1 %Sa02"'. The HVR data is displayed in Figure 5 for  all subjects (A) and for  subjects from  whom MSNA data was collected (B). Figure 5. The effect  of  IH on the hypoxic ventilatory response (HVR). Data is symbolized as individual (o) and the group mean (•) and is expressed as 1 min"1 %Sa02"' for  both pre and post IH. The HVR value was constructed from the slope of  the line when arterial oxygen saturation (Sa02) and minute ventilation (Vt) were plotted against each other. Significance  was set at p<0.05 and is represented as different  between pre and post IH (+). A: HVR data for all subjects (n=l 1). B: HVR data for  subjects from  whom MSNA data was collected (n=6). 1.2 1 . 0 - ! 0 . 8 - 1 -M 0.6 -i •s £ S E > =!. 0.4 0 . 2 - 0.0 PRE-IH POST-IH B 1.2 1 . 0 - c i» S <" £ § E > — 0.4 0.8 • 0 . 6 - 0.2 0.0 PRE-IH POST-IH EFFECTS OF IH ON THE INTERACTION BETWEEN THE S N A AND HVR. When individual data points were plotted, the maximum percent change in burst frequency  during the last 5 minutes of  the hypoxic exposure and the corresponding HVR showed a significant  correlation post IH (r=0.91 p<0.001)), but not pre IH (r=0.39, p>0.05). Figure 6 shows the relationship between HVR and the maximum percent change in burst frequency. Figure 6. The relationship between hypoxic ventilatory response (HVR) and burst frequency  during pre (o) and post (•) IH. Data is represented for  each individual (n=6). The HVR value was constructed from  the slope of  the line when arterial oxygen saturation (Sa02) and minute ventilation (V]) were plotted against each other. The burst frequency  value was obtained from  the 5 min of  the hypoxic exposure and is the percent change from  baseline in burst per minute. Burst frequency  and HVR showed a significant  correlation post IH (r=0.91, p<0.001), but not pre IH (r=0.39, p>0.05). o a. <o —« a> v C IB O CO > _l X o a. 1.2 i 1.0 0 . 8 - 0 . 6 - 0.4 0.2 0.0 o PRE-IH • POST-IH 0 50 100 150 200 250 300 % Change in burst frequency (burst min"1) EFFECTS OF IH ON THE CARDIOVASCULAR RESPONSE TO HYPOXIA. Table 10 displays the mean absolute values for  SBP, DBP, MAP, and HR for  each 5 minute period during baseline, the hypoxic exposure and recovery. Systolic blood pressure increased significantly  over time (p<0.001) with no differences  between pre and post IH (p=0.09) (Figure 7A). Diastolic blood pressure did not change as a result of  hypoxia (p=0.99) or IH (p=0.35) (Figure 7B). Mean arterial blood pressure increased significantly  during the hypoxic exposure (p<0.001), but no difference  was detected between pre and post IH (p=0.08) (Figure 7C). BASELINE HYPOXIC EXPOSURE RECOVERY 5 min 10 min 15 min 20 min 25 min 30 min 35 min 40 min 45 min 50 min PRE IH SBP (mmHg) 110.5 111.0 117.5 117.4 120.3 119.8 112.2 113.7 113.5 113.0 (2.7) (2.6) (2.6)* (2.9)* (3.1)* (3.1)* (2.9) (3.2) (3.2) (2.5) DBP (mmHg) 66.6 66.8 65.9 66.4 65.3 68.5 67.3 68.6 69.0 67.4 (3.0) (3.1) (3.6) (1.9) (2.9) (2.4) (2.8) (3.9) (3-4) (2.8) MAP (mmHg) 88.6 89.0 97.7 97.4 100.7 99.3 90.0 91.1 90.8 90.8 (2.0) (1.8) (3.6)* (4.0)* (3.8)* (4.3)* (2.5) (2.2) (2.4) (1.9) HR (beats min"1) 56.2 57.3 67.7 67.6 66.5 66.6 56.0 57.4 57.3 59.7 (2.1) (2.9) (3-5)* (4.3)* (4.2)* (3.7)* (2.9) (3-0) (2.7) (3.3) POSTIH SBP (mmHg) 110.9 113.1 119.2 120.9 117.1 119.9 116.3 114.3 114.6 115.5 (3.3) (3.6) (3.6)* (3.6)* (2.9)* " (4.1)* (3-2) (3.6) (2.9) (2.8) DBP (mmHg) 71.3 70.5 70.5 70.0 69.8 68.5 68.4 68.1 68.8 70.4 (2.5) (2.4) (2.9) (2.7) (3.2) (2.4) (2.3) (2.8) (2.3) (2.7) MAP (mmHg) 87.4 89.8 95.9 97.8 94.1 97.3 93.7 91.8 91.9 92.2 (2.9) (3.2) (3.2)* (3.0)* (2.0)* (3.7)* (2.9) (3.2) (2.7) (2.2) HR (beats min"1) 57.4 58.6 69.4 67.4 68.0 67.3 56.7 57.6 58.0 58.3 (3.1) (3.7) (4.6)* (4.4)* (3.9)* (4.2)* (3.4) (3.6) (3.4) (3-4) Absolute cardiovascular values were calculated as the mean values for  each 5 min period during the baseline, hypoxic exposure, and recovery (n=l 1). Data was acquired from  cuff  measurements. Values are expressed as means (±SE). Significance  was set at p<0.05 and is indicated as change from  baseline (*). Abbreviations: intermittent hypoxia (IH), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (MAP), heart rate (HR) Figure 7. The effect  of  IH on blood pressure. A mean value for  each 5 min period during baseline, the hypoxic exposure and recovery was calculated (n=l 1). Values are expressed as means ± SE and are symbolized as pre (o) and post (•) IH. Data was obtained from  cuff  measurements. Significance  was set at p<0.05 and is represented as change from  baseline (*). The area between the dashed lines indicates the hypoxic exposure. A: Systolic blood pressure increased significantly  over time (p<0.001). There was no difference  between pre and post IH (p=0.09) B: Diastolic blood pressure did not change as a result of  hypoxia (p=0.99) or pre post IH trial (p=0.35) C: Mean arterial blood pressure increased significantly  over time (p<0.001) but no difference  was detected between pre and post IH (p=0.08). Note the difference  in scales of  the y-axis. A 130 n uS "> >. "> 110 OT £ a. B -PRE-IH -POST-IH 10 15 20 25 30 35 40 45 50 Time (minutes) -PRE-IH -POST-IH 10 15 20 25 30 35 40 45 50 Time (minutes) -PRE-IH -POST-IH 10 15 20 25 30 35 40 45 50 Time (minutes) Figure 8 shows HR for  pre and post IH during baseline, the hypoxic exposure, and recovery. There was no difference  between pre and post IH values for  HR (p=0.94). Compared to baseline, HR increased significantly  during the hypoxic exposure (p<0.001). For both pre and post IH, HR returned to baseline values during recovery. Figure 8. The effect  of  IH on heart rate (HR). A mean value for  each 5 min period during baseline, the hypoxic exposure and recovery was calculated (n=ll). Values are expressed as means ± SE and symbolized as pre (o) and post (•) IH. Significance  was set at p<0.05 and is represented as change from  baseline (*). The area between the* dashed lines indicates the hypoxic exposure. There was no difference  between pre and post IH values for  HR (p=0.94). Compared to baseline, HR increased significantly  during the hypoxic exposure (p<0.001) and returned to baseline values during recovery. -PRE-IH -POST-IH 10 15 20 25 30 35 40 45 50 Time (minutes) EFFECTS OF IH ON MUSCLE OXYGENATION. Table 11 displays the absolute mean values for  NIRS derived variables (Hb02, HHb, tHb) for  the vastus lateralis during the entire period of  baseline and for  each 5 minute period during the hypoxic exposure and recovery. When represented in absolute terms, no difference  were observed between pre and post IH for  any of  the Beer- Lambert derived variables including Hb02 (p=0.80), HHb (p=0.64), tHb (p=0.51). Figure 9 represents percent change from  baseline for  the NIRS derived variables. The hypoxic exposure caused significant  reductions in Hb02 (p=0.01) with values increasing significantly  above baseline during recovery (p=0.02) (Figure 9A). No differences  between pre and post IH were observed Hb02 (p=0.30). Table 11. Effects  of  IH on vastus lateralis muscle oxygenation BASELINE HYPOXIC EXPOSURE RECOVERY 10 min 15 min 20 min 25 min 30 min 35 min 40 min 45 min 50 min PREIH TOI (%) 66.3 63.2 63.2 63.1 63.0 66.0 65.9 65.4 65.7 (2.3) (2.2)* (2.1)* (1.7)* (1.8)* (1.8) (1.8) (2.1) (2.1) Hb02(nMol) 3.9 2.0 2.4 3.1 3.1 6.6 6.6 5.9 6.6 (1.2) (0.62)* (0.72)* (1.2)* (1.0)* (1.5)* (1.7)* (1.6)* (1.5)* HHb ((iMol) 1.1 5.5 5.5 5.6 5.8 0.6 1.7 1.1 1.6 (1.03) (0.98)* (0.88)* (1.1)* (0.92)* (0.94) (1.27) (0.73) (0.82) tHb ((iMol) 4.8 7.4 7.9 8.7 8.9 8.8 8.8 9.0 8.2 (1.8) (1.1)* (1.1)* (1.3)* (1.2)* (1.3)* (1.3)* (1.2)* (1.5)* POSTIH TOI (%) 65.7 63.1 63.2 63.1 63.1 66.2 66.6 66.7 66.3 (2.3) (2.2)* (2.2)* (2.3)* (2.3)* (2.5) (2.5) (2.5) (2.5) Hb02 (|iMol) 3.3 1.8 2.3 2.6 2.8 6.0 6.5 7.1 7.1 (1.1) (0.72)* (0.82)* (0.77)* (0.81)* (1.2)* (1.4)* (1.3)* (1.5)* HHb (nMol) 1.0 5.7 5.2 6.0 5.9 1.0 0.5 0.9 0.5 (0.98) (0.70) (0.67) (0.94) (0.94) (0.72) (0.73) (0.76) (0.89) tHb (nMol) 3.3 6.0 6.3 7.2 7.3 5.8 5.7 5.4 5.4 (1.1) (0.81)* (0.90)* (0.91)* (1.1)* (1.6)* (1.5)* (1.8)* (1.9)* Values are expressed as means (SE). Vastus lateralis muscle oxygenation values are reported as the mean values for the entire period of  baseline and for  each 5 min period during the hypoxic exposure and recovery (n=6). Significance  was set at p<0.05 and is indicated as change from  baseline (*). Abbreviations: intermittent hypoxia (IH), oxyhaemoglobin (Hb02), deoxyhaemoglobin (HHb), total haemoglobin (tHb), tissue oxygenation index (TOI) Post IH, but not pre IH the hypoxic exposure caused significant  increases in HHb (p<0.001) with values returning to baseline during recovery (Figure 9B). No differences between pre and post IH values were observed for  HHb (p=0.63). Post IH, but not pre IH increases in tHb were observed during the hypoxic exposure (p-0.03), compared to baseline, which were maintained during the recovery period (p=0.05). The increases in tHb were mediated primarily by the increases in HHb (Figure 9C). No difference  was observed between pre and post IH (p=0.49). Figure 9. The effect  of  IH on the Beer Lambert derived measures of  haemoglobin saturation for  the vastus lateralis muscle. A mean value for  baseline and for  each 5 min period during the hypoxic exposure and recovery was calculated (n=l 1). Values are expressed as means ± SE and symbolized as pre (o) and post (•) IH. Significance was set at p<0.05 and is represented as change from  baseline (*). The area between the dashed lines indicates the hypoxic exposure. A: No difference  between pre and post IH were observed for  Hb02 (p=0.30). Compared to baseline, the hypoxic exposure caused significant  reductions in Hb02 (p=0.01). During recovery Hb02 increased significantly  above baseline (p=0.02). B: No difference  between pre and post IH were observed for  HHb (p=0.63). During the hypoxic exposure significant  increases in HHb (p<0.001) were observed. Values for  HHb returned to baseline during recovery. C: No difference  in tHb were observed between pre and post IH (p=0.49). For the post IH trial tHb increased during the hypoxic exposure compared to baseline (p=0.03) and was maintained during recovery (p=0.05). This was not observed for  the pre IH trial. Note the difference  in scales of  the y-axis. B -PRE-IH -POST-IH 10 15 20 25 30 35 40 45 50 Time (minutes) 10 15 20 25 30 35 40 45 50 Time (mintues) Time (mintues) Figure 10 displays mTOI. The percent change in mTOI from  baseline during the hypoxic exposure showed no statistical difference  between the pre and post IH (p=0.55). Compared to baseline, the mTOI was significantly  reduced (p<0.001) during the hypoxic exposure and returned to baseline values during recovery Figure 10. The effect  of  IH on the percent change in vastus lateralis muscle tissue oxygenation (mTOI). A mean value for  baseline and for  each 5 min period during the hypoxic exposure and recovery was calculated (n=11). Values are expressed as means ± SE and symbolized as pre (o) and post (•) IH. The area between the dashed lines indicates the hypoxic exposure. Significance  was set at p<0.05 and is indicated as change from  baseline (*). Compared to baseline, mTOI was significantly  reduced (p<0.001) during the hypoxic exposure and returned to baseline values during recovery. No statistical difference  between the pre and post IH (p=0.55) was observed. 105 i - PRE-IH - POST-IH 20 25 30 35 40 45 50 Time (minutes) EFFECTS OF IH ON CEREBRAL OXYGENATION. Table 12 displays the absolute mean values for NIRS derived variables for  the cerebral tissue during the entire period of  baseline and for  each 5 minute period during the hypoxic exposure and recovery. When represented as absolute values no difference  between pre and post IH were observed for  any of  the Beer-Lambert derived variables including Hb02 (p=0.80), HHb (p=0.64), tHb (p=0.78) When represented as a percent change from  baseline no difference  between pre and post IH were observed for  any of  the Beer Lambert derived variables including Hb02 (p=0.61), HHb (p=0.83), tHb (p=0.49). Compared to baseline, the hypoxic exposure caused significant reductions (p<0.001) in cerebral Hb02 with values returning to baseline values during recovery (Figure 11 A). During the hypoxic exposure significant  increases in cerebral HHb (p<0.001) were observed and values returned to baseline during recovery (Figure 9B). Cerebral tHb increases significantly  (p<0.001) during the hypoxic exposure and returned to baseline values during the recovery (Figure 9C). For cTOI (Figure 12), the percent change from  baseline during the hypoxic exposure showed no statistical difference  (p=0.64) between the pre and post IH trials. Compared to baseline, the cTOI was significantly  reduced (p<0.001) during the hypoxic exposure and returned to baseline values during recovery. Table 12. Effects  of  IH on cerebral tissue oxygenation BASELINE HYPOXIC EXPOSURE RECOVERY 10 min 15 min 20 min 25 min 30 min 35 min 40 min 45 min 50 min PRELH TOI (%) 74.3 66.4 64.6 64.7 65.1 74.0 74.3 74.2 74.4 (2.3) (2.2)* (2.5)* (2.6)* (2.5)* (2.3) (2.4) (2.7) (2.4) Hb02 (nMol) 2.7 -3.6 -3.7 -4.1 -3.7 0.59 1.3 1.3 1.1 (1.1) (0.38)* (0.47)* (0.71)* (0.74)* (0.53) (0.59) (0.57) (0.62) HHb (|iMol) -0.33 6.4 7.2 8.2 7.5 1.4 0.60 0.34 0.02 (0.26) (0.71)* (0.75)* (0.73)* (0.74)* (0.20) (0.20) (0.21) (0.20) tHb (nMol) 2.3 2.8 3.4 4.2 3.7 1.9 1.9 1.6 1.1 (0.81) (0.91)* (0.99)* (1.1)* (1.1)* (0.47) (0.50) (0.49) (0.51) POSTIH TOI (%) 75.2 66.7 67.3 66.7 67.2 75.9 76.1 76.1 75.5 (2.0) (1.5)* (1.6)* (1.6)* (1.6)* (2.5) (2.5) (2.4) (2.4) Hb02(nMol) 0.20 -5.4 -5.0 -5.1 -5.2 -0.26 0.13 0.28 0.02 (1.4) (0.69)* (0.66)* (0.69)* (0.79)* (0.66) (0.70) (0.98) (0.85) HHb (nMol) 0.23 6.7 6.6 7.5 6.6 0.56 -0.11 -0.20 -0.36 (0.65) (0.88)* (0.81)* (0.77)* (0.95)* (0.21) (0.12) (0.14) (0.15) tHb (nMol) 0.43 1.3 1.7 2.4 1.4 0.30 0.01 0.09 -0.34 (1.3) (1.2)* (1.1)* (1.1)* (1.4)* (0.54) (0.47) (0.63) (0.58) Values are expressed as means (SE). Cerebral tissue oxygenation values are reported as the mean values for  the entire period of  baseline and for  each 5 min period during the hypoxic exposure and recovery (n=6). Significance was set at p<0.05 and is indicated as change from  baseline (*). Abbreviations: intermittent hypoxia (IH), oxyhaemoglobin (Hb02), deoxyhaemoglobin (HHb), total haemoglobin (tHb), tissue oxygenation index (TOI) Figure 11. The effect  of  IH on the Beer Lambert derived measures of  haemoglobin saturation for  the cerebral tissue. A mean value for  baseline and for  each 5 min period during the hypoxic exposure and recovery was calculated (n=l 1). Values are expressed as means ± SE and symbolized as pre (o) and post (•) IH. Significance  was set at p<0.05 and is represented as change from  baseline (*). The area between the dashed lines indicates the hypoxic exposure. A: No difference  between pre and post IH were observed for  Hb02 (p=0.61). Compared to baseline, the hypoxic exposure caused significant  reductions (p<0.001) in Hb02 with values returning to baseline during recovery. B: No difference  between pre and post IH were observed for  HHb (p=0.83). During the hypoxic exposure significant  increases in cerebral HHb (p<0.001) were observed and values returned to baseline during recovery. C: No difference  between pre and post IH (p=0.49) were observed for  tHb. Increases in tHb were observed during the hypoxic exposure (p<0.001) and tHb returned to baseline values during the recovery. Note the difference  in scales of  the y-axis. A 400 o E 300 - i c 200 - A o 100 - CI o E 0 -o n -100 - X •o •8 -200 - n c -300 - C> >. X -400 - O -500 - ' " l 1 1 f - PRE-IH -POST-IH 10 15 20 25 30 35 40 45 50 Time (minutes) B - 1600 o ® 1400 = 1200 i, 1000 o £ 800 0) X 600 2 400 200 o -i -200 -PRE-IH -POST-IH 10 15 20 25 30 35 40 45 50 Time (minutes) -PRE-IH -POST-IH 10 15 20 25 30 35 40 45 50 Time (minutes) Figure 12. The effect  of  IH on the percent change in cerebral tissue oxygenation (cTOI). A mean value for  baseline and for  each 5 min period during the hypoxic exposure and recovery was calculated (n=l 1). Values are expressed as means ± SE and symbolized as pre (o) and post (•) IH. The area between the dashed lines indicates the hypoxic exposure. Significance  was set at p<0.05 and is indicated as change from  baseline (*). Compared to baseline, the cTOI was significantly  reduced (p<0.001) during the hypoxic exposure and returned to baseline values during recovery. No statistical difference  between the pre and post IH (p=0.44) was achieved. -PRE-IH - POST-IH 10 15 20 25 30 35 40 45 50 Time (minutes) CHEMICAL STIMULI DURING PRE AND POST IH. Table 9 displays the absolute values for  Sa02 and P e tC0 2 during pre and post IH for  each 5 minute period of  baseline, the hypoxic exposure, and recovery. No differences  were observed between the pre and post IH trials for  SaC>2 (p=0.83) or PetCC>2 (p=0.41). Compared to baseline, Sa02 decreased significantly  during the hypoxic exposure (p<0.001) and returned to baseline values during recovery (Figure 13). End tidal CO2 was not significantly  different  when baseline and hypoxic exposure (p=0.84) or baseline and recovery (p=0.72) were compared. D I S C U S S I O N This is the first  study to compare the effect  of  long term IH on MSNA with concurrent cerebral tissue oxygenation, muscle tissue oxygenation, cardiovascular, and ventilatory measurements. There are several new finding  from  this study. First, after  10 day IH intervention, significant  increases in MSNA burst frequency  during the 20 minute hypoxic exposure are observed which persist during the 20 minute normoxic recovery. Second, increases in burst amplitude in response to a 20 minute hypoxic exposure were observed which persisted during the normoxic recovery period; however, there was no additional augmentation of  burst amplitude with our IH intervention. Post IH caused significant  increases in HVR which showed a strong relationship with the maximum percent increases in burst frequency  and HVR. Lastly, skeletal muscle and cerebral tissue oxygenation are reduced during the 20 minute hypoxic exposure, but only skeletal muscle tHb was significantly  affected  by the IH intervention. THE EFFECTS OF HYPOXIA ON M S N A The advantage of  the microneuroraphic technique is that it measures direct sympathetic activity to the muscle vasculature and requires no inferences  or assumptions in the same way as indirect measures (i.e. catecholamine concentration and the dependence on the site of  collection, hormone production and/or clearance). Multiunit recordings of  MSNA exhibit two distinct components, both a discharge frequency  and relative amplitude. The sum of  these two components is total MSNA, an indicator of  overall sympathetic activity. It has been suggested that each component may be controlled by separate central mechanisms as each are modulated differently  in response to various stimuli (90). Therefore,  it is important to examine all aspects of  the MSNA signal. To discern the effects  of  IH on burst frequency,  amplitude, and total MSNA, the present investigation used a 20 minute isocapnic hypoxic exposure with a hypoxic stimulus of-80%  Sa02. An Sa02 of  80% was chosen to ensure equal peripheral chemoreceptor engagement between subjects and it has been suggested that this is the threshold required to elicit hypoxic induced sympathoexcitation (148). The FiC>2 required to produce an SaC>2 of  80% varied between subjects, ranging from  -10-15%. We intended to examine only the effects  of  low oxygen on the SNS response, therefore  we held PetC02 at eucapnia levels and spontaneous breathing was permitted. This study specifically  addressed how the increases in MSNA observed during a 20 minute hypoxic exposure and normoxic recovery period may be modulated after  10 days of  IH. ACUTE MSNA RESPONSE TO THE HYPOXIA EXPOSURE. During the pre IH trial, the 20 minute isocapnic hypoxia exposure significantly  increased burst frequency  above baseline by a mean of ~ 130%. This was observable within the first  5 minutes of  the hypoxic exposure and remained elevated during the entire 20 minute hypoxic exposure. This observation is consistent with the work of  others. Xie et al. (172) reported burst frequencies,  of-170%  after  20 minutes of  acute hypoxia combined with either isocapnia or hypercapnia. Morgan et al. (103) showed burst frequency  increases of  -220% after  acute asphyxia (combined hypoxia and hypercapnia). Because these two these investigations used the exact same level of  hypoxia (Sa02 = - 8 0 % ) , the difference  in the magnitude of  burst frequencies  reported in the current investigation and that reported by others can be attributed to the additional effects  of  CO2 on sympathetic outflow  and some differences  in experimental design. Hypercapnia has additive effects  on the increases burst frequency  during hypoxia. The sympathetic response to CO2 can be the result of  direct activation of  central chemoreceptors or the result of  increased sensitivity of  the peripheral chemoreceptors to hypoxia (156). The effect  of  CO2 in our study is not a factor  as we were successful  in maintaining end tidal concentrations at eucapnic levels. With regards to total MSNA, we observed an increase of  -150% in total MSNA during the 20 minute hypoxic exposure in the pre IH trial. This is in line with the work of  Cutler et al. (20) who showed a -200% increase in total MSNA following  20 minute hypoxic apnoeas. During the 20 minute hypoxic exposure we observed a -120% increase in MSNA burst amplitude compare to baseline. There was no difference  between pre and post IH trials. Burst amplitude is not typically reported for  various reasons. First, common analysis techniques have been not been established for  the computation of  burst amplitude (83, 90, 92). Additionally, controversy exists regarding what burst amplitude represents physiologically. It has been suggested that burst amplitude, acquired from  multi unit recordings, reflects  changes in the population or type of  neurons recruited, as different  neurons can vary in their sympathetic response characteristics (i.e. conduction velocities, size) (89, 116). It is not likely that the increases in burst amplitude are the result of  an altered recruitment of  a particular population or type of  neuron, given the large variation in amplitudes observed in a multi-unit recording during a sympathetic stress, such as hypoxia and the fact  that few  neurons are in actual contact with the microelectrode. It is more likely that alterations in burst amplitude are representative of  changes in the actual number of  activated neurons in contact with the microelectrode, regardless of  their type (90, 116). Another reason burst amplitude may not be reported is that there is relatively little information  regarding the predictability of  burst amplitudes (89), whereas methods of predicting burst frequency  are well established (6). In human studies only burst frequency  and total MSNA are typically reported when examining the hypoxia induced sympathoexcitation. Xie's group (172) did mention burst amplitude citing no changes in response to a 20 minute hypoxic exposure, although the data were not shown. Only one other study in humans reported burst amplitude response with hypoxia in humans. Leuenberger et al. (83) reported an increase of  -210% in total amplitude after  25-30 minutes of  hypoxia (123 ± 36 to 255 ± 50 mm min"1 for  baseline and exposure, respectively). An appreciation of  the changes in burst amplitude can be constructed from  studies that report both burst frequency  and total MSNA (burst amplitude is a factor  in the calculation of  total MSNA). For example, Cutler et al. (20) reported that during hypoxic apnoeas total MNSA and burst frequency  increased ~200% and ~175%, respectively. What could account for  the additional 25% increase in total MNSA? It is reasonable to speculate that increases in burst amplitude contributed to the increases in total MSNA Cutler's study. Our data support this speculation. Although the observed rise in burst frequency  was greater than the observed rise in burst amplitude, both variables mediated the rise in total MSNA. It has been shown that hypoxia can augment burst amplitude in animal preparations (90, 91). In anaesthetized cats exposed to systemic hypoxia, direct renal sympathetic nerve activity showed increases burst amplitude (91). In the same preparation, when baroreceptor activity was increased, burst frequency  rose whereas burst amplitude did not. These data suggest that burst frequency  and amplitude may be controlled for  by separate central mechanisms. Therefore, amplitude and frequency  may respond differently  to acute hypoxia. Furthermore, increases in renal nerve burst amplitude, confirming  our findings  of  increases in MSNA burst amplitude with hypoxia. MECHANISMS CONTROLLING THE ACUTE M S N A RESPONSE TO THE HYPOXIA EXPOSURE. The cause of  the sympathetic activation during hypoxia can be the result of  three relatively distinct pathways: activation of  peripheral chemoreceptors, central chemoreceptors, or baroreceptors. Figure 13 depicts the three pathways in which sympathetic activation can be generated in response to hypoxia, as well as the simultaneous respiratory activity and is a modified  version to that described by Guyenet (53). It is well documented that peripheral chemoreflex  activity is related to increases sympathetic outflow  and it is likely the primary cause of  sympathoexcitation observed in humans exposed to systemic hypoxia (140, 158). We suspect that this pathway is a Figure 13. Neural pathways in the medulla that control ventilatory and sympathetic activity in response to hypoxia (modified  from  Guyenet, 2000). This pathway can be initiated by both peripheral and central (indicated by an astrix) chemoreceptor stimulation and baroreceptor disengagement. Consequently, a cascade of  events within the medullary cell groups that generate sympathetic and phrenic nerve activity will be triggered (see text for abbreviations and a detailed description). • CHEMORECEPTORS' HYPOTHALAMUS* PONS A5 REGION' RVLM* PHRENIC NERVE ACTIVITY SYMPATHETIC OUTFLOW major contributor to the observed sympathoexcitation during hypoxia in our study, although we do not have direct evidence to support this hypothesis conclusively. The carotid bodies can respond to hypoxia by generating sensory afferent  signals which are then transmitted from  the carotid sinus nerve to the CNS and terminate in a specific  group of  medullary cells called the nucleus tractus solitarius (NTS). The neurons within the NTS then relay excitatory signals to other cell groups within the medulla, including the RVLM, the pre-Boetzinger region located in the intermediate ventral lateral medulla (IVLM), and the caudal ventral lateral medulla (CVLM). These areas have neural linkages and are primarily responsible for  generation of  sympathetic tone, respiratory rhythm, and blood pressure control, respectively. The physiological consequences of  these structural linkages has been observed in both reduced animal preparations and in intact humans. Direct recordings of  cellular activity within the neurons of  the RVLM show strong correlation to post ganglionic sympathetic nerve activity (i.e. MSNA) suggesting that there is little modulation within the pre ganglionic neurons or the spinal ganglia. In both humans and animals respiratory rhythmicity has been observed in recordings of  direct post ganglionic sympathetic activity (89, 145, 152, 175). Respiratory rhythmicity is possible by various pathways (see Figure 13). First, a common pool of  neurons in the NTS that control respiratory and sympathetic activity concurrently in response to peripheral chemoreceptor stimulation can be activated with hypoxia an influence  the activity of  the sympathetic and respiratory system. Alternatively, respiratory rhythmicity could also be the result of  excitatory activity of  pre- Boetzinger cells, as there are neural connections between this region and the RVLM. It has also been suggested that the NTS contains a subset of  neurons that may be excited by peripheral chemoreceptor stimulation and project directly to the RVLM, without an intervening relay within the respiratory network (depicted in Figure 13 by thick arrow). The relationships between the neural networks that respond to peripheral chemoreceptor activation have been demonstrated experimentally. In anaesthetized animals selective chemical blockade of  cells within the NTS that project to the respiratory networks (IVLM and pre- Boetzinger region) omitted the respiratory oscillations in sympathetic activity, but did not alter the overall magnitude of  sympathoexcitation (79). This is evidence that a separate set of  neurons exist that project directly from  the NTS to the RVLM. Because the activity and patterning of  the RVLM is under some influence  of  central respiratory networks, but is not dependent on these pathways for  the generation of  sympathetic activity suggests that neural projections from  the NTS that control the both the RVLM and pre-Boetzinger, or the connections from  the pre- Boetzinger to RVLM are activated concurrently. In humans, the relationship between central respiratory and sympathetic neural control has been shown. Sympathetic activity is modulated by ventilation as MSNA patterns are unique to each phase of  the breathing cycle (25, 26, 151, 152). Compared to the exhalation phase, during inhalation, sympathetic outflow  is reduced via the influence  of  inhibitory signals from pulmonary mechanoreceptors (152); however, alterations in ventilation do not affect  the overall magnitude of  sympathetic activity (152). Collectively, when the results from  animal and human studies are taken together, it is evident that sensory afferents  from  the carotid body can be relayed from  the NTS to the RVLM, with no interaction or dependence on the ventilatory control centers. As a result increased sympathetic outflow  may occur without affecting  the ventilatory system. Our data support this possibility as MSNA and ventilation increase simultaneously during the initial minutes of  the hypoxic exposure bust over time ventilation declined and MSNA remained elevated (for  more detail see section: EFFECTS OF IH ON THE VENTILATORY RESPONSE TO HYPOXIA). Our data suggest that the direct pathways from  the NTS to the RVLM may be independently facilitated  during hypoxia. Direct activation of  central chemoreceptors can generate increases in sympathetic outflow.  Cell groups within the medulla that are involved in the control of  sympathetic activity, such as the A5 region of  the pons, the hypothalamus, and the RVLM (indicated by an asterix in Figure 13) can detect systemic hypoxia. In rodents, systemic hypoxia has been shown to directly activate the presympathetic neurons of  the RVLM, regardless of  whether or not the carotid sinus nerves are intact. Severe levels of  hypoxia (Fi02 < 10%) were required to directly elicit increased activity of  these RVLM presympathetic neurons (154). In our study, to achieve an Sa02 of  80%), Fi02 ranged between —10-15%. Consequently, it is unlikely that central chemoreception was a major influence  in the sympathoexcitation in our study, but it cannot be excluded for  certain. Lastly, the rise in MSNA observed during hypoxia may be mediated by a cascade of events leading to activation of  pressure sensitive cardio-pulmonary baroreceptors. During hypoxia, an initial reduction in blood pressure is caused by abrupt increases in heart rate, decreases in cardiac output (85), and vasodilatation of  peripheral vessels (10, 16, 54, 84, 93, 95, 122, 147, 157). Reductions in blood pressure can result in baroreflex  disengagement (72, 159) causing increases in afferent  signal transmission which synapse in the NTS and CVLM (see Figure 13). The CVLM has neural extensions to cell groups within the RVLM. In an attempt to regulate blood pressure these baroreceptor inputs may play an important role in the reflex increases in MSNA in response to physiological stress (141), including hypoxia. Tamisier et al. (157) tested the role of  baroreceptor activation in the hypoxia induced increases in MSNA. By blunting sympathetic vasoconstriction via the blockade of  alpha-receptors, distinct local forearm vasodilatation occurred. The authors concluded that under non-pharmacological conditions this vasodilatation was masked by sympathetic vasoconstriction. We did not measure baroreceptor function  or take measurements of  peripheral vasodilatory production in the current study. Nonetheless, the contribution of  baroreceptor activation in the hypoxia induced increases in sympathetic activity cannot be ruled out. PERSISTENT MSNA DURING NORMOXIC RECOVERY. In both the pre and post IH trials, the increases in burst frequency,  burst amplitude, and total MSNA generated during the hypoxic exposure were maintained for  the duration of  the 20 minute normoxic recovery period. Persistent MSNA following  the removal of  the chemical stimuli is a well documented phenomenon in humans (20, 103, 156, 157, 171, 172) and it has been reported to remain elevated for  as long as 180 minutes (20). Morgan et al. (103) were the first  to document the persistent sympathetic activity during a 20 minute normoxic recovery period (60 minutes for  two subjects). In this study -66% of  increase in burst frequency  generated during the 20 minute asphyxic exposure was maintained. In a subsequent study Xie et al. (172) showed that the ~170% increase in burst frequency  induced by an isocapnic hypoxic exposure remained almost unchanged throughout the entire 20 minutes of  normoxic recovery. The mechanisms responsible for  the sustained elevation in MSNA after  a brief  exposure to hypoxia are not clear. The persistent sympathoexcitation has been attributed to hypoxia exclusively, as hypercapnic hyperoxia (103) and hypercapnic normoxia (172) did not result in persistent MSNA during recovery. It is not likely that residual chemical stimuli (i.e. retention of low oxygen pressures in carotid body and/or chemoreceptive medullary cells) are the cause of the persistent sympathetic activity. We showed that SaC>2 values had returned to baseline almost immediately into normoxic recovery indicating that the pressure of  oxygen in the arterial blood had normalized, likely permitting normalization of  cellular oxygen pressures throughout the body. If  normalization of  cellular oxygen pressures were not the case, elevated ventilation would be expected via continued carotid body stimulation and activation of  respiratory neural networks. As discussed in the earlier, since severe hypoxia was not experienced, direct central chemoreceptor alterations are not likely to contribute to the increase in MSNA and therefore persistent of  MSNA. Instead the mechanisms causing the persistent MSNA observed after hypoxia may be due to long term modulation in the sympathetic control centers in the CNS and may be dependent increased carotid sinus nerve activity during the hypoxic exposure. This modulation could include a combination of  continued neurotransmitter release and/or neural transmissions. These are the same mechanisms thought to be involved in the development of sympathetic activity in response to acute to hypoxia. It has been postulated that the persistent MSNA in humans is the result of  continued afferent  signal transduction from  carotid body activity post hypoxic exposure because persistent increases in ventilation are observed in dogs (13). Conversely, isocapnic hypoxia in anesthetized cats showed no persistent effect  on carotid body afferent  activity after  the removal of  the hypoxic stimulus (7). No persistence in ventilation is observed in any human study of  hypoxia and the following  normoxic recovery. To explain the observed divergence in ventilatory and sympathetic responses post hypoxia from  both animal and human studies it has been suggested that in humans the gain in chemoreflex  control of  sympathetic activity could be larger than that for  ventilatory activity in humans (103). If  this were the case, some sort of  undetected residual chemical stimuli within the carotid bodies could cause sustained afferent  signal transmission An alternative explanation is that hypoxia may engage the sympathetic and respiratory control centers differently.  If  hypoxia is sensed directly by the CNS centrally, independent of carotid body inputs, perhaps the effect  on the RVLM and ventilatory control centers are different.  As discussed above, direct central chemoreception is possible by numerous cell groups within the medulla and these areas could remain active after  hypoxic exposures (53, 113). Long term facilitation  of  a number of  central mechanisms, dependent and independent of  carotid body inputs, have been postulated in contributing to the persistent MSNA observed after  hypoxia (113). As a result of  carotid body afferent  activity, cellular and neural processes in the RVLM could remain active after  the termination of  the hypoxic stimulus. Specifically,  stimulation of the carotid body during the hypoxic exposure could potentate neurotransmitter release in the CNS maintaining sympathetic output post exposure. Sympathoexcitation may be maintained at the level of  the preganglionic neurons, where hypoxic stimulation potentates neurotransmitter release from  sympathetic ganglia in a similar way to that seen after  electrical stimulation (101). Additionally, evidence suggests the specific  mechanisms at the level of  the spinal cord are capable of  detecting and responding to systemic hypoxia (137). Hypoxia could directly facilitate conduction and synapses in neural pathways in charge of  sympathetic transmission in the same way that electrical stimulation has elicited long term sympathetic transmission in the brainstem. As opposed to the chemoreception theory, enhanced baroreceptor disengagement could be the primary mechanism in the persistent MSNA after  hypoxic expsoures (55, 56, 72, 159). It has been suggested that vasodilatation precedes sympathetic vasoconstriction as it causes a reduction in blood pressure and deactivation of  baroreceptor inputs to the NTS. Pharmacological blockade of  alpha adrenergic receptors that mediate sympathetic vasoconstriction permitted hypoxia induced vasodilatation (157). In addition, with continued infusion  of  the alpha adrenergic receptor blocker, vasodilatation persisted for  as long as 30 minutes after  termination of  the hypoxic (157). Therefore,  peripheral vasodilatation as a result of  hypoxia may continue into recovery without pharmacological intervention, causing baroreceptor disengagement and could be rooted in the cause of  the persistent MSNA in an effort  to maintain blood pressure. Again, because we did not measure the role of  the baroreceptors in the current study we cannot make conclusions regarding this mechanism's contribution to the observed persistent in MSNA. MSNA POST 10 DAYS OF IH. Post IH, we observed a ~ 1 5 0 % increase in burst frequency  in response to a 20 minute hypoxic exposure that was maintained through the entire period of recovery and was significantly  higher than that observed in the pre IH trial ( - 1 2 0 % ) . Increases in burst frequency  after  IH indicated that the occurrence of  neuronal firing  has increased. Burst amplitude increased -120% in response to the 20 minute hypoxic exposure and was maintained throughout recovery. The rise in burst amplitude post IH was identical to the pre IH trial, indicating that this component of  MSNA was not affected  with our IH intervention. Based on our results, it appears that the number and/or the population of  neurons recruited do not change with long term exposure to IH. Moreover, because we saw different  response of  burst amplitude and frequency  to our IH intervention, leads us to hypothesize that these two components can be modulated differently  with IH. With regards to total MSNA during the post IH trial, a mean increase of  -200%) was observed within the first  10 minutes of  the hypoxic exposure, rising to -220% during the final  10 minutes. During recovery total MSNA was maintained at -200% of baseline values. The patterns in total MSNA were mediated primarily through the increases in burst frequency.  A trend towards statistical significance  (p=0.06) was observed when pre and post IH were compared and was likely not achieved due to the fact  that burst amplitude did not undergo any modulation with IH. It is likely that the same mechanisms involved in the development of  sympathetic activity in response to acute hypoxia and its persistence during recovery are involved in the increased sensitivity of  the sympathetic nervous system after  IH. Because no other study has sought to describe the effects  of  IH delivered in a laboratory setting on MNS A in humans, an explanation of  our findings  requires speculation. To put our results into context of  the current literature, we must draw from  studies that measured sympathoexcitation at altitude in healthy humans (both directly via MSNA and indirectly via catecholamine production), long-term IH studies in animals, and pathological models of  IH in humans. The only other investigation to acquire direct measurements of  sympathetic activity was conducted by Hansen and Sander (57). They recorded MSNA at sea level and after  4 weeks at 5260 m and showed burst frequency  increased by 32 burst min"1, or increases of  -300% of baseline. This substantial increase in burst frequency  occurred with mean SaC>2 values of  -85%, which is relatively high considering that an SaC>2 of  80% is the reported threshold required to elicit sympathoexcitation (149). In comparison, our intervention increased burst frequency significantly,  but only by a mean of  7 burst min"1, or increases of  -166% of  baseline . The most obvious explanation for  the discrepancy between our study and that of  Hansen and Sander is the total amount of  time exposed to hypoxia: 10 hours at an SaC>2 of  -80% delivered for  one hour for  10 days versus - 672 hours at a sustained SaC>2 of  -85%, respectively. Additionally, the larger increases in MSNA in the Hansen and Sander study could be attributable to the additive effects  of  hypobaria, the physiological effects  of  hypocapnia (cellular alkalosis), and anxiety associated with travel to altitude (138). Other investigations have used urine and plasma catecholamines, such as norepinephrine (NE) as an indirect measure of  sympathetic activity (18) as sampling is relatively easy compared with the microneurograhic technique. Norepinephrine primarily represents the activity of sympathetic nerves that terminate in muscle vasculature (30, 99). Therefore,  measurements of NE and MSNA have shown a strong relationship (83). With long term exposure to hypoxia at altitude increases in NE have been demonstrated (4, 12, 18, 99, 138). However, because it is an indirect assessment, results have been inconsistent (138). Therefore,  caution must be taken when interpreting the results. For example, it has been shown that hypoxia can increase both NE spillover and clearance and one must account for  both mechanisms to obtain an accurate assessment of  hypoxic mediated increases in NE concentration (83). Further studies of  the effects  of  IH sympathoexcitation should include simultaneous collection of  both NE and MSNA to discern the relationship between these two measurements and these two techniques. In animal models of  long term hypoxia, it has been postulated that peripheral chemoreflex  control is altered after  long term exposure to hypoxia; therefore,  because peripheral chemoreceptor afferents  have excitatory neural linkages in the CNS, one could speculate that this altered control of  peripheral chemoreflexes  may have downstream implications on the MSNA response after  long term IH. In anesthetized goats, carotid body discharge progressively increased during a sustained level of  hypoxia indicating an increased sensitivity of  the carotid body to hypoxia (114). If  this finding  is true, it is reasonable to speculate that carotid body discharge can progressively increase with a sustained exposure to hypoxia in humans and since carotid body afferents  terminate in the RVLM progressive activation could contribute to the enhanced MSNA. This is a possible mechanism in the persistent MSNA in our study, as we used a sustained hypoxic exposure of  -80% Sa02, although we cannot conclude conclusively, as we did not obtain measurements of  carotid body afferent  activity. Further evidence in humans supports the hypothesis that peripheral chemoreflex  and sympathetic control are altered after  long term exposure to hypoxia (102, 103, 171). Unique augmentation of  carotid body reflexes  and control of  sympathetic nerve traffic  were observed in healthy humans exposed short term intermittent hypoxic apnoeas (19). The same findings  were observed in patients with OS A, a pathological model of  IH (107). The repetitive apnoeic events during sleep cause repeated bouts of  hypoxia and hypercapnia which act via the chemoreflexes  to increase sympathetic nerve activity. During non-apnoeic periods burst frequency  is elevated in those with OSA compared to healthy controls (43.0 ± 4.0 versus 21.0 ± 3.0 bursts min"1) (107). Long term exposure to IH during sleep is likely the cause of  the increased sympathoexcitation leading to other physiological consequences, such as increase normoxic blood pressure; however, it is difficult  to demonstrate a clear causal relationship. In rodents, work by Fletcher's group modeled their IH interventions to replicate the hypoxic conditions experienced in OSA. They show that 35 days of  IH significantly  affected  sympathetic outflow  to the muscle vasculature (40), kidney (38, 42), and adrenal medulla (5) and that this response is dependent on intact carotid chemoreceptors (32). Furthermore, this group has shown that increases sympathetic outflow  has physiological ramifications,  such as increased normoxic blood pressure (33-35, 39)(for  further  details see section: EFFECTS OF IH ON THE CARDIOVASCULAR RESPONSE TO HYPOXIA). Although our subjects only underwent 10 days of  IH, our data support the concept that repeated exposure to IH in OSA or in the rat model could elicit a sustained increase in MSNA during non-apnoenic periods and in the absence of  the hypoxic stimulus. However, we did not see any alteration in cardiovascular measurements with our model of  IH. Molecular and cellular alterations within the peripheral chemoreceptors and central nervous system could contribute to the enhanced MSNA observed with long term IH. Chronic IH showed increased production of  reactive oxygen species causing functional  plasticity in carotid body sensory activity in experimental animal (128, 132, 144). The sensory facilitation  of the carotid body may contribute to persistent reflex  activation of  sympathetic nerve activity due to the overlapping central structures controlling ventilation and sympathetic activity (120). However, this possibility likely has a minor role at best as we did not see any augmentation in ventilation during the hypoxic exposure post IH while we saw enhanced MSNA. More convincing is the suggestion that central mechanisms undergo long term potentation due to IH, leading to enhance neurotransmitter release or a facilitation  of  synaptic transmission in areas in charge of  sympathetic outflow,  such as the RVLM (53, 113). Furthermore, within the cells of the CNS, genomic processes that respond to hypoxia could facilitate  the sustained MSNA. In the medullary regions expression of  a genomic factor,  c-fos  has been shown to increase after  chronic IH in rabbits (59) and rodents (50). The production of  these 'first  response genes' indicate changes in neuronal genetic transcription which can lead to physiological alterations, such as sympathetic outflow,  further  down stream. EFFECTS OF I H ON THE VENTILATORY RESPONSE TO HYPOXIA Ventilation increased significantly  from  baseline during the 20 minute isocapnic hypoxic exposure, mediated by an increase in both breathing frequency  and tidal volume. The pattern of change in ventilation in response to the 20 minute isocapnic hypoxic exposure was identical for the pre and post IH trials, indicating that the IH intervention did not alter the sensitivity of  the carotid body to sustained hypoxia. Alterations in carotid body sensitivity is reasoned to be the mechanism for  augmentation of  ventilatory response to progressive hypoxia in animal and human models (127, 140). Ventilation trended towards a decline after  ~5-8 minutes of  the hypoxic exposure. This phenomenon is known as the hypoxic ventilatory decline (HVD), and is extensively documented (47, 124, 143). The occurrence of  HVD may be the result of  down regulation in the nerves of  the CNS in charge of  ventilation (i.e., the pre-Boetzinger region) (112). Alternatively, HVD may be due to a reduced phrenic nerve output, which has been is reported during isocapnic hypoxia in surgically manipulated cat preparations (100). A reduction in tidal volume was the primary cause of  HVD in the current study. Ventilation returned to baseline values within the first  5 minutes after  the removal of  the hypoxic stimulus. Therefore, LTF of  the carotid body is unlikely in humans as ventilation returns to baseline during the normoxic recovery (12, 19, 20, 47, 77, 85, 104, 123-125). During both pre and post IH and prior to the 20 minute hypoxic exposure, an HVR procedure was performed.  The HVR value obtained from  the post IH day was significantly higher than that obtained from  the pre IH trial, nearly doubling. Other studies conducted in humans have produced similar results (44, 69, 88). In a recent study by Katayama et al. (69) 3 hr of  daily IH (Fi02= -12%) caused HVR to increase from  0.26 ± 0.12 to 0.59 ± 0.21 L min"1 %Sa02"1 after  one week and 0.23 ± 0.12 to 0.61 ± 0.37 L min'1 %Sa02"' after  two weeks, resulting in a increase of  38 - 44%. In the present study, 10 days of  IH at Sa02 of  80% provided a similar hypoxic stimulus, which augmented ventilatory sensitivity. The current study is comparable to that of  Katayama's as our HVR values increased 49% from  the pre IH trial and absolute HVR values were 0.30 ± 0.07 and 0.61 ± 0.29 L min"1 %Sa02"' for  pre and post IH, respectively. The carotid body plays an obligatory role in the HVR. Bilateral carotid body tumor resection results in abolition of  the ventilatory response to hypoxia, due to peripheral chemoreflex  failure  (60, 158). Increases in HVR following  IH in humans can be attributed to an enhanced carotid body chemoreceptor reflex.  To support this hypothesis is the observation that continuous hypoxia increases carotid body sensory activity in goats (114). The increases in HVR after  IH appear to be greatly affected  by the paradigm employed - dependent on factors such as pattern and severity of  the hypoxic exposures (119, 121, 128, 134). Peng and Prabhakar (121) showed that in rats the hypoxic sensory response of  the carotid body was significantly enhanced only after  short durations of  IH (hypoxia lasting several seconds cycled with normoxia). Our daily hypoxic stimulus may have acted in a similar way, increasing the sensory response of  the carotid body and causing an enhanced HVR. Short exposures to IH may cause unique engagement of  cellular mechanisms, such as oxygen sensing free  radicals, heme proteins, and facilitation  of  ion channels which in turn induce sensitization of  the carotid body (132, 133). To account for  the observed increases in HVR in humans after  long term IH, it has been reasoned that the first  few  exposures of  IH could cause a time limited sensitization of  the carotid body, engaging pathways within the CNS. It is possible that these mechanisms may remain elevated with long term IH, facilitating  an enhanced ventilatory response. Recent work in rodents suggest that central mechanism that respond to carotid body inputs are acting to facilitate  a change in HVR after  chronic hypoxia. Dopamine is an important inhibitory transmitter involved in central neural synapses and has been shown to respond to peripheral chemoreceptor stimulation. Dwinell's group (29) used chronic hypoxia to address the role of  central mechanisms in the alteration of  HVR by testing the involvement of  the dopamine- 2 receptor. With chronic hypoxia, time-dependent reductions in the dopamine-2 receptor were observed in ventilatory control centers in the brain and the authors suggest that these changes could modulate the ventilatory response to hypoxia. Although we did not measure the chemical changes in the CNS in our IH intervention, we cannot rule out the possibility that such changes may have occurred and may be the cause of  the increases in HVR in our study. It is possible that centrally mediated changes in areas unique to the ventilatory control, such as the IVLM and the pre-Boetzinger region are mediating the changes in HVR in our study. EFFECTS OF I H ON THE INTERACTION BETWEEN THE SYMPATHETIC ACTIVITY AND VENTILATION After  the IH intervention we showed a strong relationship between the maximum change in burst frequency  during the last 5 minutes of  the hypoxic exposure and HVR. This relationship was not observed pre IH. Coupled alterations in the ventilatory and sympathetic systems have been previously shown after  long term exposure to hypoxia. Asano et al. (4) showed a significant  correlation between urine NE and tidal volume at after  long term hypoxia at altitude, suggesting that the response of  the ventilatory and sympathetic systems are in some way related to each other and controlled for  together. In experiments that addressed the relationship between breathing phase and the sympathetic response more directly, opposing data is presented. In humans it has been shown that within breath variations in MSNA exist (25, 26, 145, 151, 152). During inhalation, which is the end phase in the determination of  tidal volume, activation of pulmonary stretch receptors cause reflex  reductions in sympathetic outflow  (152). Therefore, when the lungs are at their largest volumes, sympathetic activity is at its lowest values. Our data support this concept in two ways. First, MSNA remained elevated, or increased during the latter stages of  the hypoxic exposure while ventilation experienced a decline mediated primarily by a reduction in tidal volume. Secondly, maximal burst frequency  value for  correlation analysis with HVR was taken from  the last 5 minutes of  the hypoxic exposure where HVD is observed (Figure 6). At this point HVD may have permitted this maximal rise in MSNA. Not all trends in ventilatory and sympathetic activity occurred in parallel in the current investigation. Divergence in the activity of  these two systems was observed during both the pre and post IH trials. First, as mentioned previously, during the 20 minute hypoxic exposure, ventilation and MNSA increased concurrently, but within ~5-8 minutes of  sustained hypoxia, ventilation declined whereas MSNA continued to rise. Secondly, although MSNA remained elevated after  the removal of  the hypoxic stimulus, ventilation returned to baseline measures. Noteworthy, in the present study, the two variables used for  correlation were not collected at identical time points. The HVR was collected before  the start of  the 20 minute exposure and the maximum burst frequency  was obtained from  the final  5 minutes of  the hypoxic exposure. It is not clear how an indicator of  hypoxic acclimatization (i.e. increased HVR) and high sympathetic activity can exist together after  IH. This is contradictory given that increased tidal volumes during hypoxia will act to reduce sympathetic activity through inhibitory lung mechanoreceptors. The most likely explanation is that central modulation occurs with IH in areas of  the medulla that have common neural extensions in the RVLM and pre-Boetzinger region. Such modulations would include long-term potentiations of  synaptic transmission in the brain and cellular/genomic alterations. EFFECTS OF I H ON THE CARDIOVASCULAR RESPONSE TO HYPOXIA During the 20 minute exposure to hypoxia, MAP and SBP increased and returned to baseline values within 5 minutes of  normoxic breathing. The DBP was not significantly  altered during the hypoxic exposure or recovery. There was no effect  of  the 10 days of  IH on blood pressure response during baseline to the 20 minute hypoxic exposure or recovery. Pre and post IH, values for  SBP and MAP were nearly identical. Other laboratory interventions using human subjects and employing some paradigm of  IH have shown increases in blood pressure. Foster et al. (44) showed that 12 days of  short duration IH, and not long duration IH increased the SBP and DBP sensitivity to an acute hypoxic exposure. The change in SBP sensitivity (r=+0.68; p<0.05) and the change in DBP sensitivity (r=+0.73; p<0.05) was related to the change in HVR. They attributed this response to a potentially greater stimulation of  the carotid body with the short duration protocol. It can be speculated that an enhanced carotid body afferent  outflow  will lead to augmentation of  central mechanisms in charge of  sympathetic activity and vascular tone. After  8 hours of  severe IH for  35 days in rodents, Fletcher and colleagues (41) showed increases in resting blood pressure of  -13 mmHg which is dependent on the carotid body and sympathetic activity. Taken together, the present study likely did not find  significant  augmentation of  blood pressure because the sustained hour long exposures did not effectively  activate the carotid body and/or central mechanisms. The time line of  the experiment may have been too brief  suggesting that more than 10 days of  IH or a more severe hypoxic stimulus is required to show alterations in cardiovascular responses. Additionally, analysis of  cardiovascular measurements during steady state hypoxia may not detect the changes in sensitivity of  after  IH. In the present study, heart rate rose significantly  during the 20 minute hypoxic exposure and this augmentation was not different  between pre and post trials. Our data is supported by the work of  Foster et al. (44) who show that heart rate sensitivity was not affected  by a 12 day IH intervention. More research is needed to explain why heart rate response to hypoxia do not change with IH, as heart rate variability a measure of  autonomic control of  heart rate has been shown to be altered. Like blood pressure, heart rate may have required longer or more severe hypoxic exposures. Heart rate follows  patterns in respiration and is affected  by the interaction of lung mechanoreceptors, baroreceptors, and chemoreceptors. There was no difference  in minute ventilation, blood pressure, and chemical stimuli between pre and post IH trial, and therefore  it can be reasoned that heart rate is not different. EFFECTS OF I H ON MUSCLE OXYGENATION During both pre and post IH, the 20 minute hypoxic exposure resulted in significant reductions in Hb02 and increases in both HHb and tHb. The mTOI represents vastus lateralis muscle oxygen saturation and during hypoxia, and significant  reductions were observed. Considering their dependence on Sa02, NIRS derived variables are reported to closely match the changes in oxygen pressure in arterial blood during hypoxia (115); our data confirm  this observation. With normoxic recovery HHb and mTOI returned to baseline values where as Hb02 and tHb remained elevated. Patterns in vastus lateralis HHb, Hb02 and TOI were not different  when expressed as either percent change or in absolute terms after  the IH intervention. However, tHb showed significant  elevations from  baseline post IH, but not pre IH. Values for  muscle tissue oxygenation are dependent on blood flow,  metabolism, vasoactive mechanisms, and SaC>2. We anticipated that markers of  tissue oxygenation such as mTOI and Hb02 would be reduced as they are dependent on oxygenation of  the arterial blood (58). During normoxic recovery, when SaC>2 returned to baseline values skeletal muscle oxygenation measures also return to baseline values. This occurred despite the persistent increases in MSNA and the potential increase in vasoconstriction drive. To achieve this normalized muscle oxygenation in recovery, it is possible that a continued production of vasodilator elements may occur to balance sympathetic vasoconstriction. However, we did not collect these measures and cannot conclude this for  certain. It has been demonstrated that tHb is strongly correlated with measures of  muscle vessel conductance and is a valid method for  assessing muscle vasodilatation (169). Therefore, comparisons can be made between studies that use blood flow  and NIRS to examine hypoxia induced vasodilatation. Measurements of  tHb represent blood volume and are a surrogate for blood flow  (87). Based on the current findings  of  vascular dysfunction  in skeletal muscle vessels post IH (122) we expected that our IH intervention would cause vascular dysfunction  resulting in a reduced dilatory ability in response to hypoxia and causing reductions tHb. Furthermore, based on our hypothesis that MSNA would be augmented after  IH we expected to observe a smaller increase in tHb, mediated by sympathetic vasoconstriction. The balance between local vasodilatation and sympathetic vasoconstriction will dictate the alterations in blood flow,  vascular resistance, and blood volume. The purpose of vasodilatation with exposure to hypoxia is to increases vascular conductance and limit the fall  in oxygen delivery to muscle when the oxygen content of  the arterial blood is low or restricted due to hypoxia mediated sympathetic vasoconstriction. The primary mechanism of  hypoxia induced vasodilatation is unknown, and is likely due to a combination of  mechanism. Endothelium derived nitric oxide (10) and adenosine (96, 147), are a means of  skeletal muscle vasodilatation observed during hypoxia. The interaction of  these two elements is shown to vary along the vascular tree (95), which may explain the divergent findings  between studies using different  non- invasive methods of  assessing vasodilatation, such as plethysmograph, Doppler ultrasound, and NIRS. The NIRS technique assesses tissue oxygenation, but more specifically  venous blood affluent.  Only small portions of  the NIRS signals are derived from  arterial blood oxygenation where as blood flow  and resistance measurements are acquired from  the arterial side. The haemodynamic responses of  the muscle will be dependent on whether or not hypoxia has been administered acutely or chronically. With acute systemic hypoxia in intact humans increases in blood flow  and reductions in vascular resistance have been reported (84, 85, 157). In a study by Leuenberger et al. (83), 25-30 minutes of  hypoxia at a mean Sa02 of  74% caused a significant  rise in forearm  blood flow  and a decrease in forearm  vascular resistance. In the same study, skin blood flow  and vascular resistance did not change implying that if  vasodilatation in the forearm  did occur, it must be manifested  locally within the vasculature of  skeletal muscle. This idea is supported by our data. Both muscle HHb and tHb increase during the 20 minute hypoxic exposure and represent increases in blood volume within the area under the probes. In a separate study Leuenberger et al.(85) showed an alternative trend. Voluntary apnoea was associated with a decrease in leg blood flow  and an increase in vascular resistance and these observations were most evident during hypoxic apnoea compared to hyperoxia apnoea. The authors suggested that the increases in MSNA induced during the hypoxic apnoeas stimulated the arterial chemoreceptors, leading to increased vasoconstriction and therefore  impeded blood flow and augmented vascular resistance. Tamisier et al. (157) showed that reductions in forearm  blood flow  and increases in forearm  vascular resistance during hypoxia (mean Sa02 = -80%) are in part affected  by sympathetic activity. They showed that reductions in forearm  blood flow  and increases in forearm  vascular resistance could be reversed by alpha receptor blockade, thereby eliminating sympathetic constriction within the local vasculature. Interestingly, they showed that during normoxic recovery, vasodilatation persisted with continued infusion  of  the alpha receptor blocker permitted after  the termination of  hypoxia. In our study, it can be reasoned that the continued vasodilatory release during recovery combined with the maintenance of  increased MSNA permitted the NIRS measurements to return to baseline or exceed baseline values during recovery. Caution must be taken when assessing blood flow  changes during hypoxia via Doppler ultrasound, the method common among the abovementioned studies. Specifically,  Doppler reveals velocity measurements, which assumes a constant lumen diameter. Given that sympathetic activity increases with hypoxia, and reports show changes in BP with hypoxia, it is likely that the diameter of  the vessel is decreased during hypoxia. To our knowledge, there have been no studies that have examined the effects  of  long term IH on skeletal muscle haemodynamics or tissue oxygenation in humans. However, we can look to studies using isolated vessel preparations to provide insight to what may be occurring in vivo after  chronic exposure to hypoxia. In rats, isolated vessel preparations of  the gracilis muscle show a reduced dilatory sensitivity to hypoxia (122). The authors attribute these finding  to molecular changes within the vessel, implicating a reduced bioavailability of  nitric oxide (122) and suggest an impairment of  the vessel to protected against reductions in tissue oxygenation with acute hypoxic exposures. Others have shown that during acute hypoxia constrictor response to NE is reduced after  chronic hypoxia (95), suggesting that vasodilatation, mediated through the SNS may be favoured.  Additionally, to preserve tissue oxygenation structural changes such as arteriolar remodeling and capillary angiogenesis can occur with hypoxia (63, 81, 146). The fact that we saw increases in tHb post IH compared to pre IH suggests that mechanisms acting to increase blood volume and therefore  preserve tissue oxygenation are enhanced after  10 days of IH. Our results go against the reports cited above where vasodilatory mechanisms are compromised after  long term exposures to hypoxia. It must be considered that because the NIRS technique measures oxygenation on the venous side primarily, it may not be able to detect changes occurring at the arterial side of  the vascular tree where much of  the vascular changes with IH have been reported. EFFECTS OF I H ON CEREBRAL OXYGENATION With acute exposure to 20 minutes of  hypoxia, indices of  cerebral oxygenation decreased, which returned to baseline values during the 20 minutes of  recovery. An appreciation of  this reduced cerebral oxygenation can be achieved by examining the specific  oxygen associated chromophores. In our study, cerebral HbC>2 was reduced, and HHb and tHb were increased. The large increase in HHb mediated the reduction in cTOI, an indicator of  cerebral oxygen saturation. In the current study, no effect  of  the IH intervention was observed in during exposure to 20 minutes of  hypoxia in any measurement acquired by NIRS in the region of  tissue examined in the brain. Based on previous examinations of  cerebral vessel haemodynamics during hypoxia in . vivo and in isolated vessel preparations, we anticipated that the post IH response to the 20 minute hypoxic exposure would demonstrate reductions in cerebral oxygenation measured via NIRS. Specifically,  we hypothesized that tHb would be reduced post IH, indicating a reduced blood flow  and an impairment of  the cerebral vessels to respond to hypoxia. Additionally, we expected that the reduction in tHb would be mediated by a reduction in HHb. Our data show no indication of  differences  in HHb or tHb between pre and post IH. Nonetheless, our hypotheses were based on convincing data, and it is likely that our intervention failed  to show significant  differences  due to the method of  analysis, and equally likely, the short duration and mild severity of  the hypoxic intervention. Cerebral oxygenation during hypoxia will be affected  by various mechanisms and stimuli, including alterations in blood flow  (77, 123, 166), tissue metabolism (110, 111), and CO2 tension (2, 65, 73, 124). Like the skeletal muscle, NIRS and blood flow  measurements correlate well in the brain (165) and tHb can be used as an indicator for  blood volume (58). Cerebral oxygenation is also directly influenced  by changes in SaC>2 (44, 77, 160). Unique to the cerebral vasculature is a phenomenon known as autoregulation, which tightly regulates blood flow  to the brain and must be considered when assessing the response of  the cerebral vasculature to hypoxia. In response to acute hypoxia it is documented that vasodilatation of  cerebral vessels occurs, mediating increases in blood flow  and it can be reasoned that this functions  to prevent tissue hypoxia. The mechanisms by which vasodilatation in the cerebral circulation occur is primarily mediated through nitric oxide (122). In the current study we see a marked increase in tHb and HHb, indicating reductions in cerebral oxygenation and increased blood volume. These findings  have been confirmed  by others (44). With exposure to long term IH (14 days), the bioavailability of  nitric oxide in the cerebral circulations is severely blunted. This results in a reduced vasodilator responsiveness to acute hypoxia (122). Using NIRS, Foster and colleagues (44) show that exposure to daily hypoxia reduces in the sensitivity of  cerebral tissue oxygen saturation to hypoxia. The differing  results between our study, and that of  Foster's group can be attributed to the method of  analysis. We examined the changes in NIRS parameters during a sustained level of  hypoxia at SaC>2 of  80% where as they looked at the changes in the sensitivity of  these parameters during a progressive exposure. Opposite to the NIRS assessment of oxygenation sensitivity, increases in the sensitivity of  blood flow  to acute variations oxygen was observed after  IH (5 nights, 8 hours/night, simulated altitude-4,300 m, Sa02=~85%) (77). In patients with OSA, hypoxic apoenas is reported to cause increases in cerebral blood flow velocity (CBF) which appears to be modulated by increases in MAP or some other unknown mechanism controlled for  by some autonomic mechanism in the cerebral circulation (136). Perhaps we did not observe alterations in our measurements of  cerebral tissue oxygenation, as we did not see increases in BP variables as a result of  our IH intervention. Although directionally opposite, it can be argued that reductions in cerebral tissue oxygenation measured via NIRS and increases blood flow  measure by transcranial Doppler (TCD) indicate similar physiological changes in response to hypoxia. Depending on the level of the vascular tree, vascular response to vasodilator elements may be different.  Using TCD, blood flow  is typically measured at the middle cerebral artery, a relatively large vessel that is highly responsive to nitric oxide while NIRS measurements generally represent tissue oxygenation or blood oxygenation on the venous side which may not respond to nitric oxide in the same way (87). Additionally divergent findings  between "blood flow"  or more specifically  blood volume changes with NIRS and other methods can be attributed to certain methodological factors. NIRS uses oxygen, based on its association with haemoglobin to track changes in blood volume (117). Using this method, it must be assumed that changes in tissue metabolism and blood flowdo  not occur. It is well documented that reductions in the metabolic rate of  the CNS neurons occur with hypoxia (113), as do alterations in blood flow  (123) and therefore  complicate the applications of  this technique. Lastly, measurement of  blood flow  with Doppler is possible only when the innsonated vessel diameter does not change. This assumption may not be met when alterations in constrictor activity are known to occur with hypoxia. The rationale for  the lack of  statistical significance  between pre and post IH NIRS measures in the muscle and cerebral tissue is four-fold:  1) the IH intervention was either too short or not severe enough to cause vascular dysfunction;  2) NIRS is not sensitive to the changes in vascular dysfunction;  3) the method of  analysis is not an appropriate way to detect changes in vascular dysfunction  using NIRS; 4) large inter-subject variability in the response to hypoxia confounded  our results and not the lack of  physiological alterations caused by the IH intervention. CRITIQUE OF METHODS/LIMITATIONS Because pre and post IH hypoxic exposures occurred on different  days, it is possible that the significant  differences  observed in MSNA burst frequency  and HVR were the result of  day- to-day variability. Using the same techniques employed in the present study and conducted in the same laboratory, HVR values show a day-to-day coefficient  of  variation of  27% (75). Burst frequency  values acquired on separate days are highly repeatable with less than 15% variability (162), but this is not a consistent finding  (163). Based on these findings  we are confident  that the changes observed in MSNA burst frequency  and HVR are the result of  our 10 day IH intervention. It is possible that the initial rise in sympathetic activity and its persistence was the result of  other factors,  such as anxiety induced from  masked breathing, long periods of  sitting, or the laboratory procedures (161). A familiarization  day was included to reduce this possibility and acquaint the subjects with the procedures. Additionally, if  the anxiety associated with the unfamiliarity  of  laboratory procedures were the cause of  the increased sympathoexcitation, it would be expected that the MSNA values would be higher during the pre IH trial. In other studies employing a similar protocol, anxiety was ruled out as a possible cause for  the increased sympathetic activity, as time control subjects did not show increases in MSNA (20, 103). In the present study, sympathetic nerve activity was assessed from  post ganglionic sympathetic nerves leading to the muscle vasculature in the lower leg. This activity represents that of  whole body sympathetic activity to muscle vasculature, and does not necessarily represent the activity directed to other organs systems. Therefore,  speculation as to what is occurring in the kidney, heart, and brain cannot be made. Shifts  in electrode position, activation of mechanoreceptors, or motor neuron activity may have confounded  our results. To eliminate the influence  of  these factors,  data was excluded from  analysis if  a baseline shift  or an increase in the density of  the spikes occurred. To avoid the influence  of  inter-individual variation in MNSA during rest and hypoxia, strict guidelines were followed  pertaining to inclusion/exclusion criteria (see SUBJECTS under the M E T H O D S section). Regardless, to make comparisons between subjects and for  statistical purposes M S N A is expressed as percent change from  baseline. Both peripheral and central stimulation of  oxygen sensitive chemoreceptors can play a role in the development of  sympathoexcitation in response to acute or chronic hypoxia. In an intact human we are unable to assess the relative contribution of  these pathways to the increased MSNA. Regardless, we suspect that sympathoexcitation arises primarily from  peripheral chemoreception. Although we collected both MSNA and blood pressure data, we are unable to implicate chemoreceptor or baroreceptor engagement as the primary cause for  the development and maintenance of  the heightened MSNA. To more accurately discern the contribution of  these mechanisms in humans, a broad range of  blood pressure values, measures of  central venous pressure, and collection of  endogenous vasodilatory elements would be required. Arterial oxygen saturation, arterial pressure of  CO2 (PaC02) and BP were assessed non- invasively by finger  pulse oximetry, PetC02, and by finger  pulse photoplethysmography, respectively. Finger pulse oximetry does not account for  changes in temperature and pH, which affect  the association of  oxygen and haemoglobin. It is not likely that changes in temperature or pH occurred in our subjects, as the experiments were conducted during rest and PetC02 was held constant at baseline levels. Furthermore, it has been shown that pulse oximetery accurately reflects  Sa02 when values obtained from  the oximeter are > 70% (51) and our subjects remained at -80% through out the hypoxic exposure. The PetC02 has been reported to be accurate at ranges between 30 to 55 mmHg during hypoxia. Considering our subjects were held at isocapnic levels of  -42 mmHg, it can be expected that these values accurately reflect  PaC02. Beat-by-beat BP devices have been reported to be accurate at tracking changes in blood pressure (118); however, the ability of  these devices to track changes in blood pressure is dependent on the quality of  the pressure wave (51). To ensure accurate readings, beat-by-beat blood pressure was calibrated to cuff  measurements taken during baseline and cuff  measurements acquired thought out the protocol were used for  statistical analysis. Near infrared  spectroscopy is non-invasive technique used to monitor the oxygenation of haemoglobin in the sampled tissue. Some have suggested that NIRS measurements reflect  blood flow  and tissue metabolism. Although the NIRS signals will be affected  by these factors,  it must be recognized that NIRS only tracks oxygen's association with haemoglobin. Furthermore, NIRS cannot differentiate  between the location of  the haemoglobin molecule, be it in the arterial or venous side. In the brain, it has been demonstrated that 5% of  the blood is situated in the capillaries, 20% in the arteries, and with the remainder located in the venous side (87). As a result, NIRS measurements of  the cerebral tissue likely reflect  venous haemoglobin oxygenation, and not tissue oxygenation. In skeletal muscle at rest, ~70% of  the blood is situated in the venous capacitance vessels, suggesting that NIRS measurements taken from  the muscle also reflect  venous hemoglobin oxygenation and not that of  skeletal muscle tissue (11). The NIRS signals can be affected  by insufficient  light shielding, optode placement, and optode shifting.  To minimize the influence  of  these factors,  optodes were fixed  to the skin with double sided tape covered with a dark clothe. We ensured accurately placement over both the vastus lateralis avoiding the iliotibial band and cerebral tissue avoiding the sinuses and temporal muscles. Sections of  data were excluded due to subject movement or a loss of  signal. It should be noted that the NIRS unit used in the present study cannot distinguish between the haemoglobin and myoglobin, and therefore  the reported Hb02, HHb, and tHb signals are representative of  both molecules. CONCLUSIONS The primary finding  from  the current study is that 10 days of  IH caused a significant increase in MSNA burst frequency  and a trend towards an increase in total MSNA during a 20 minute isocapnic hypoxic exposure. Indices of  sympathoexcitation are maintained throughout the 20 minutes of  normoxic recovery. It has been previously reported that long term exposure to hypoxia causes increases in the HVR, and this is supported by our work. A new finding  from our study is that the increase in HVR is significantly  correlated to the maximal increase in burst frequency.  Because burst frequency  and HVR are modulated concurrently after  10 days of  IH, suggests that these physiological responses may have common central controllers. A new finding  is that increases in burst amplitude occur with exposure to acute hypoxia which is maintained during recovery. This indicates that the number or population of  neurons recruited during the exposure is altered. Furthermore, we are the first  to report that 10 days of  IH did not elicit a change in burst amplitude. Therefore,  and increase in MSNA as a result of  long term exposure to IH will be mediated by increases in burst frequency,  or how often  a signal is transmitted. Cardiovascular, ventilatory, and cerebral tissue oxygenation measurements were not significantly  affected  by the 10 days of  IH, although they were affected  by acute exposure to hypoxia and our results are consistent with the current literature. No effect  of  our IH intervention on these measurements is likely due to the fact  that the hypoxic stimulus was either too short, not severe enough, or that steady state analysis is not a sensitive enough method to detect changes. This is the first  study to show that IH in humans can significantly  increase on MSNA during hypoxia and recovery. Because OSA is characterized by IH, elevated MSNA in our model may prove useful  in examining the mechanisms involved in the development of  the increased sympathoexcitation in this population. L I T E R A T U R E R E V I E W With exposure to low oxygen, numerous adaptive responses at the microvascular, organ system, and organismal level are activated to preserve oxygen delivery and transport in an effort to avoid cellular hypoxia. At the organismal level for  example, peripheral chemoreceptors can detect reductions in arterial oxygen pressures and through a series of  pathways increase ventilation to preserve oxygen uptake and delivery. At the mircovascular level, vasodilatation of terminal arterioles and increased recruitment of  capillaries allows tissues to extract more oxygen from  a limited supply. The pattern by which hypoxia is experienced is an important consideration. Both continuous and intermittent exposures to hypoxia cause unique physiological responses, and it is likely that the distinctive cellular and molecular processes intrinsic to each paradigm are responsible. Regardless of  the pattern, long term exposures to hypoxia will cause physiological changes with the organism - some appear to be beneficial,  while others have harmful consequences. Protein production, ion channel alterations (133), activation of  transcriptional enzymes (50, 59), induction of  genomic pathways (45), erythropoiesis (48), angiogenesis (144), and increases in the hypoxic ventilatory response (131) are just a few  ways to protect against cellular hypoxia. However, as a result of  hypoxia increases in sympathetic outflow  may have negative cardiovascular implications (32, 82). This is evident in patients with obstructive sleep apnoea (OSA), a pathological condition characterized by long term intermittent hypoxia (IH) during sleep. This population is reported to develop diurnal hypertension, mediated primarily through persistent sympathoexcitation (68, 86, 106, 107, 168). The purpose of  this review is to outline the molecular processes by which a biological system can detect and respond to hypoxia and how these processes function  to modulate the activity of  the sympathetic nervous system (SNS). The concurrent alterations in the ventilatory, cardiovascular, and circulatory (or haemodynamic) systems observed with hypoxia will be briefly  covered, and put into context as they relate to the SNS modulations. The various measurements of  the sympathetic activity to acute and chronic hypoxia will be discussed and data from  laboratory interventions, excursions to altitude, and patients with OSA will be presented. OXYGEN SENSING PATHWAYS AND THE SYMPATHETIC NERVOUS SYSTEM Both peripheral and central chemoreceptors play a key role in detecting and responding to hypoxia (29, 53, 68, 126, 127). It is not likely that these pathways function  exclusively to produce the sympathoexcitation observed with hypoxia. Instead, each step along the oxygen sensing pathway may contribute, to a varying degree, to the sympathetic activation and may be uniquely modulated with long term exposures to hypoxia. Numerous other stimuli that often accompany hypoxia, such as changes in atmospheric pressure and CO2 tension can contribute to the observed sympathetic activation. Details of  these stimuli are beyond the scope of  this review and the reader is referred  elsewhere (53, 80, 94, 125, 138) . PERIPHERAL CHEMORECEPTORS Peripheral arterial chemoreceptors, specifically  the carotid bodies, are primarily responsible for  detecting and responding to systemic hypoxia in most environmental and experimental conditions. In response to acute or chronic hypoxia, early work by Forester et al. (43) demonstrated that intact carotid bodies in goats were essential for  the acute ventilatory response and ventilatory acclimatization. More recently, Peng and colleagues (119) have demonstrated that sensory discharge from  the carotid body, and the magnitude of  such discharge is increased after  IH in rodents. Furthermore, this group has shown that the response of  the carotid body is dependent on the pattern of  hypoxia administered (121). Short, cyclical bouts of hypoxia, and not long continuous exposures selectively augment the response to low oxygen. It has been proposed that the cyclic exposures elicit unique production of  oxygen free  radicals, which alter the redox state of  various proteins within the cells of  the carotid body, affecting signal transduction. In humans, the important role of  the carotid body has been demonstrated on a more phenotypic level. Carotid body resection results in the abolishment of  a ventilatory response to hypoxia (60, 62, 158). It has been extensively reported that the ventilatory response to hypoxia can be increased with long term exposure to hypoxia of  varying degrees and patterns (44, 71, 76). Garcia and colleagues (49) showed that with chronic hypoxia (3,800 m altitude), maximal increases in HVR where achieved after  2 weeks, as there was no additional effect  after 8 weeks of  exposure. In an earlier study this group showed that an equivalent level of  hypoxia (FjCh of  0.13 =-3800 m altitude) delivered intermittently for  12 days elicits similar changes in HVR) (48). The use of  animal preparations has significantly  advanced our current understanding of cellular signaling within the carotid body in response to hypoxia, and has allowed hypotheses to be made about what occurs in vivo. Cellular and molecular mechanisms by which the carotid body responds to hypoxia are brought about by the activation of  two types of  specialized cells: glomus cells, which are neuronal in nature and sustanticular cells which act as a type of  support cell (133). Within the glomus cells, chemical stimuli can activate a number of  cellular processes to cause membrane depolarization, the release of  neurotransmitters, causing stimulation of afferent  nerve endings. Thus, the first  step in a series of  nervous transmissions that contribute to the sympathetic response to hypoxia is initiated. With regards to glomus cell depolarization and transmitter release, two pathways have been suggested as the primary oxygen sensors. One hypothesis supports that reduced oxygen tensions activate heme proteins (and some non-heme proteins). These proteins could lead to the production of  reactive oxygen species which can facilitate  neural transmission and controls the release of  neurotransmitters (132). An alternative theory implicates the inhibition of  the K + ion channel which leads to an increase of  cytosolic Ca (130). Calcium is partly responsible for  neurotransmitter release and is an important regulator in gene transcription (128, 130, 132). To respond to hypoxia, it is likely K+ ion channel and the redox state of  heme proteins do not function  exclusively. Instead each pathway may dominate during a particular severity of  hypoxia, in the presence of  other chemical stimuli, and may experience unique alternations with long term hypoxia. A phenomenon known as long term facilitation  (LTF), has been observed in the carotid body after  hypoxic exposures, despite the normalization of  blood gases and blood pressure and may contribute to the persistent sympathetic nervous activity (120, 134). In animals, LTF of carotid body afferents  occurs after  hypoxic exposures and is characterized by sustained elevations in breathing (120) and sympathoexcitation (131). Peng et al. (120) showed that the development of  LTF in the carotid body is dependent on the pattern in which hypoxia is administered, and implicated a unique activation of  ROS in the cyclic paradigm. However, sustained elevations in breathing have not been reported in humans while persistent sympathetic activity is consistently observed (20, 103, 156, 157, 171, 172). To explain the divergent findings with regard to LTF of  the carotid body, it has been postulated that in humans, the gain of ventilatory sensitivity is less that the gain of  sympathetic sensitivity within the CNS (103). CENTRAL NERVOUS SYSTEM In vivo, direct central chemoreception cannot be assessed. It is likely that direct activation of  central chemoreceptors plays a minor role in human studies where increased sympathetic activity has been cited, as FiC>2 values are typically above 10% and Sa02 values are not often  below 80%. Therefore,  much of  the centrally mediated increase in sympathetic outflow during hypoxia is the result of  peripheral afferents  inputs that terminate within the medulla, including those from  the carotid body, phrenic nerve, and arterial baroreceptors. The interaction of  the carotid body synaptic transmissions with the medulla is likely the primary peripheral contributor to centrally derived sympathoexcitation. Alterations in ventilatory activity, which is closely linked to sympathetic activity, confirm  the important relationship of  central processing of  afferent  information  from  peripheral chemoreceptors Dwinell et al. (29) exposed rats to a maximum of  7 days of  chronic hypobaric hypoxia (P1O2 = 80 torr). As a result of  the intervention, ventilation increased and was dependent on the dopamine D-2 receptor, an indicator of  peripheral and central interaction. The authors concluded that chronic hypoxia causes changes in dopamine D-2 receptor that could result in changes in the ventilatory response to hypoxia. Sensory afferent  transmission from  the carotid body travel via the carotid sinus nerve causing a cascade of  synapses within the CNS (refer  to Appendix B) (53). The nucleus tractus solaris (NTS), a regulatory center for  sympathetic activity, receives afferents  from  the carotid body. Here, interneurons synapse with a number of  other control centers, namely the rostral ventral lateral medulla (RVLM), a region in charge of  sympathetic tone. The neurons of  the RVLM contain two types of  cells that produce elements regulating sympathetic outflow.  CI cells produce catecholamines which regulate vascular tone via the sympathetic nervous system and non-C 1 cells can increase sympathetic activity by the production of  proteins, such as glutamate. The pre ganglionic neurons from  the RVLM extend to the spinal cord and synapse with their respective post ganglionic neurons, whereby efferent  sympathetic transmission is directed to the blood vessels and organs. The pre and post ganglionic neurons from  the RVLM to the organ systems and vasculature are different  (refer  to Appendix B). As a result it is likely that regulation and modulation of  sympathetic activation to each region will be distinctive. In animal preparations, it has been demonstrated that during severe hypoxia (FiC>2<10%) central chemoreceptive cells located in the hypothalamus, thalamus, pons, and medulla are capable of  responding directly to hypoxia via enhanced neurotransmitter release (53, 137) and can therefore  contribute to sympathoexcitation. This is achieved mainly through the alteration in biochemical pathways within the central chemoreceptive cells leading to the production of  c-fos and june-B, genetic markers of  neuronal activity. Hirroka et al. (59) showed that in conscious rabbits, 60 minutes of  moderate hypoxia (Fi02 = 10%) increased the expression of  Fos in many neurons of  the NTS, parts of  the medulla, pons, and several regions in the midbrain and forebrain.  The activation of  these early response genes can trigger a cascade of  genomic transcriptions, coding for  other mediators, potentially effecting  phenotypic outcomes. For example, hypoxia can increase c-fos  expression and has been linked to the up regulation of  HIF- 1, an oxygen sensitive transcriptional complex that drives the expression of  downstream genes, resulting in the production of  erythropoietin and vascular endothelial growth factor  (45). Interneurons of  the RVLM extend to other regions within the medulla that can modulate sympathetic activity and respiration. Noteworthy, is the interaction of  the RVLM and the pre- Boetzinger region, the respiratory rhythm generator. The pre-Boetzinger region receives inputs from  the phrenic nerve. The activity of  the phrenic nerve is increased with hypoxia since ventilation is increased. Therefore,  sympathetic transmissions from  the RVLM can be influenced by activity in the pre-Boetzinger region. Arterial baroreceptors and phrenic nerve activity can affect  the hypoxic induced sympathoexcitation as they both have neural inputs terminating the medulla (94). Both of  these inputs were factored  in the control of  MSNA in a comprehensive study by St Croix et al. (152). They showed that the maximal and minimal activation of  the sympathetic nervous system occurred at end expiration and end inspiration, respectively. The changes in MSNA that occurred with each breath were negatively related to diastolic blood pressure (DBP) and had no relationship with changes in intrathoracic pressure. Reductions in DBP demonstrate baroreflex  unloading and reflect  changes in baroreflex  sensitivity and/or threshold. Therefore,  the authors concluded that alterations in MSNA derived via respiratory rhythmicity were secondary to alterations in carotid sinus baroreceptors. To measure sympathoexcitation in response to hypoxia, quantification  of  numerous markers have been acquired. Sympathetic nerve activity, collected via the microneurographic technique, is the only direct assessment of  autonomic activation and has been applied to renal and splanchnic nerves and various skeletal muscle nerves. The use of  microneurography has been limited due to accessibility and technical expertise. The information  acquired from microneurography represents whole body sympathetic activation to muscle vasculature and is collected via peripheral nerves in humans, typically the peroneal. Similarly, indirect measures of whole body sympathetic activity have been made via the collection of  urine and blood catecholamines. Indirect indices of  sympathetic activity to organ systems are possible by collection of  heart rate variability and plasma renin activity. In humans, acute hypoxia has been studied in a laboratory setting using masked breathing or hypobaric chambers while chronic hypoxia in humans has been conducted at altitude and in hypobaric chambers. MUSCLE SYMPATHETIC NERVE ACTIVITY Morgan and colleagues (103) sought to discern the effects  of  acute hypoxia on MSNA in humans and whether this activity persisted with the return to normoxia. The motivation for  their query came from  observations made in experimental animals where increases in ventilation were maintained after  the removal of  the hypoxic stimuli. To address their question 20 minutes of sustained hypoxia combined with hypercapnia (Sa02=80% and PetC02= eucapnia +5torr) was administered. Compared to baseline, the asphyxic stimulus caused a sudden increase of  220 ± 28% in sympathetic burst frequency.  The novel aspect of  their study was that during the 20 minute normoxic recovery burst frequency  remained significantly  elevated even with the normalization of  cardio-respiratory variables. Hypoxia was implicated as the primary stimulus as a hypercapnic-hyperoxic trial (Fj02 = 5% and PetC02 - eucapnia + 5 torr) saw a smaller rise in sympathetic minute activity (197 ± 32%), with values returning to baseline upon resumption of room air breathing. The observation of  persistent sympathoexcitation with the return to normoxia prompted subsequent studies, which systematically addressed the effects  of  various patterns of  hypoxia and stimuli. In correspondence with Morgan's findings,  Xie et al.(172) showed that 20 minute of sustained isocapnic hypoxia and hypercapnic normoxia evoked increases in MSNA; again, persistent MSNA was only observed in the hypoxic trial. Even when delivered in a discontinuous fashion  (20 seconds of  asphyxia separated by 40 seconds of  normoxia; Sa02 = 79- 85%; PetC02 = eucapnia +3-5 torr), hypercapnic hypoxia resulted in sympathetic activation rose 175 ± 12% above baseline and was sustained after  the removal of  the chemical stimuli (171). Culter and colleagues (19) examined the role of  apoena and CO2 combined with discontinuous hypoxia on the prolonged elevation in MSNA. This experimental design was constructed in an effort  to replicate the conditions of  OSA and potentially unveil the mechanisms involved in the sustained sympathoexcitation common with this disease. However, among the discontinuous hypoxic challenges, no differences  were detected between apoenic, isocapnic, or hypercapnic groups but all groups did show that MNSA persisted for  180 minute post exposure. Again hypoxia was implicated as the primary stimulus in the development and maintenance of  MSNA. How could hypoxia cause the sustained increased MSNA in humans post exposure? Because invasive measurements could not be acquired, inferences  regarding the control mechanisms were made. These authors supported the idea that peripheral chemoreceptor activation acting through some facilitated  central mechanisms was the cause and functioned  in a way analogous to LTF in the carotid body. Specifically,  changes within the medullary regions that controlled sympathetic outflow  and meditate the persistent efferent  sympathetic activity could include a maintained excitatory neurotransmitter release, synaptic memory, or enhanced post ganglionic neuronal activity. These hypotheses seem to be reasonable mechanisms for  the persistent MSNA in humans. Within the CNS, the gain of  the chemoreflex  control of sympathetic outflow  may be higher than that for  ventilation (103). Ventilation normalized during recovery, and although ventilatory and sympathetic control centers share common structures, ventilation is also controlled for  by separated regions in the medulla (pre-Boetzinger). Therefore,  perhaps the chemoreflex  control of  the SNS was selectively facilitated  post exposure. An alternative view has been postulated, suggesting that the arterial baroreceptors are the primary mechanism for  the initial rise and the continued maintenance in sympathetic activity (55, 56, 156, 157). Baroreflex  engagement can result from  reductions in vascular tone and blood pressure, therefore  unloading these pressure sensitive fibers.  This was originally though to be a secondary response to buffer  carotid body vasoconstriction and maintain vascular tone. It is well established that dilatation (54, 83, 122, 157, 169, 170), and therefore  reductions in vascular tone, occurs in the muscle vasculature in response to hypoxia and is maintained during normoxic recovery. Endothelium derived nitric oxide and adenosine (10, 84, 93, 95, 122, 147) contribute to the vasodilatation observed in skeletal muscle during hypoxia. The interaction of  these to elements varies along the vascular tree, but ultimately their actions lead to an increased vascular conductance to limit the fall  in oxygen delivery (95). Consequently, reductions in vascular resistance and blood pressure are observed (55, 72) leading to an unloading of  the arterial baroreceptors. Furthermore, local peripheral vascular mechanisms causing vasodilatation and baroreceptor engagement may persist during recovery and could be rooted in the cause of  the persistent MSNA (20) with short term exposures to hypoxia. Only one investigation has looked at the long term effects  of  hypoxia on MSNA in healthy humans. Hansen and Sander (57) showed that after  4 weeks of  chronic hypoxia at altitude (5360 m) MSNA burst frequency  was higher compared to that at sea level. The elevated MSNA was maintained at altitude despite either disengagement of  the peripheral chemoreceptors or baroreceptors via administration of  supplemental oxygen (100%) or saline, respectively. After descent (3 days at normoxic sea level), burst frequency  remained significantly  elevated - a comparable phenomenon to the persistent MSNA seen during the normoxic recovery and following  an acute exposure to hypoxia (103, 155-157, 171, 172). In a pathological model of  chronic intermittent hypoxia (IH), persons with OSA experience hypoxic apnoeas during sleep which causes marked increases in MSNA that persist during the daytime, even when breathing pattern and blood gases are normal (168). The nocturnal hypoxic apnoeas have been proposed as the primary cause of  the sympathoexcitation in this population (107) and this is supported by several lines of  evidence. First, normoxic burst frequencies  have been reported to be over 50% higher in patients with OSA compared to healthy controls who do not experience apnoeic events. Secondly, the elevated MSNA in response to hypoxia is dependent on the stimulation of  the carotid body in OSA patients (108, 149). Lastly, when treated for  the hypoxic apnoeas with a continuous positive airway pressure device, normoxic MSNA was significantly  reduced (105, 108, 168). These data support the hypothesis that the hypoxic apnoeas are the primary stimulus for  the sympathoexcitation observed in OSA. Numerous other factors  could contribute to the sympathoexcitation in OSA, such as spontaneous arousals, airway obstruction, and hypercapnia. Additionally, obesity is a risk factor in the development of  OSA and it has been proposed that obesity may contribute to the high sympathetic activity. However, during normoxic breathing subjects of  normal weight without OSA, obese without OSA, and obese with OSA showed 41 ± 3, 42 ±3, and 61 ± 8 bursts per 100 heartbeats, respectively indicating that obesity did not contribute to the elevated sympathetic activity in this investigation (106). CATECHOLAMINES Catecholamine production, in particular norepinephrine (NE) has been extensively examined during hypoxia. The brain, heart, sympathetic nerve endings, and the adrenal medulla can all produce NE in response to hypoxia. As a consequence HR and myocardial contractility, vessel contractility, blood flow  distribution and energy substrate mobilization are affected  (8). The results from  studies that have used NE as a marker of  sympathoexcitation have been equivocal. This is likely due to the nature of  non-invasive methods as it increases the probability of  error. With regards to NE specifically,  values will be dependent on thecite of  collection (urine, arterial blood, venous blood) and the production and clearance rates which are known to change with hypoxia. Nonetheless, sympathoexcitation using NE as a marker has been shown to increase with hypoxic exposure. Plasma and urine NE has been shown increase in response to hypoxia achieved via high altitude (99), hypobaric chamber (66), and laboratory administration (83). Leuenberger et al (83), observed a net increase in arterial NE after  an acute exposure of 25-30 minutes of  hypoxia delivered via a mask (SaC>2 =~74%) despite an increase in NE clearance. Others have demonstrated different  results. In an earlier investigation Rowell et al. (139)showed that although acute hypoxia (Fj02 of  8-12%) increases MSNA, no rise in venous NE was observed. It was suggested that hypoxia may enhance clearance of  NE as a result of  an alteration of  blood flow  or neuronal uptake of  NE. Therefore,  the dynamics (production and metabolism) of  NE during both acute and chronic hypoxic exposures must be considered. The effects  of  chronic hypoxia on NE have also been addressed. In humans, exposure to 21 days of chronic high altitude (4300 m) increased arterial NE by 84% (99). Nine weeks at altitude saw arterial NE concentrations increase 3.7 fold  and were caused by higher whole body NA spillover (12). Alternative to the findings  of  Leuenberger's group, this study reported similar NE clearance rates pre and post the sojourn to altitude. Unique control of  the heart during a sympathetic stress is possible due to the fact  that the heat is innervated by a separate series of  pre and post ganglionic neurons and is controlled for  by a separate set of  centrally located neurons in the RVLM (Appendix C). In vivo, direct neural recordings of  cardiac sympathetic nerve activity are not possible. However, non-invasive measurements of  heart rate variability (HRV) have been used to assess the relative contribution of  the sympathetic and parasympathetic nervous systems on cardiac autonomic control. This is possible by calculating the fluctuation  in the time intervals between heart beats. Using the ECG waveform,  an algorithm is set and the intervals are analyzed via spectral analysis giving high (> 0.15-Hz; PH) and low (0.0- to 0.15-Hz; PL) frequencies.  Low frequencies  represent sympathetic activity and high frequencies  represent parasympathetic activity of  the heart. The ratio of  these frequency  bands gives an indication of  what system is dominating and controlling heart rate. Measurements of  HRV have been made at altitude and with hypoxic exposures administered in the laboratory. With brief  exposure simulated altitude (3500 m for  2 hrs) HRV is altered (174). Increases in heart rate are observed at altitude, thereby shortening the time interval between heart beats and this indicates increases in the relative contribution of  the sympathetic control of  heart rate (relative decrease in parasympathetic systems indicator). Chronic exposed to altitude (4350 m for  6 days) also affected  HRV over time (17). Low frequency-to-high frequency  ratios increased from  day 1-2 and day 5-6. With acclimatization, the reductions in parasympathetic and rise in sympathetic control of  heart rate tended to be reversed (17). The reduction in sympathetic control of  heart rate with acclimatization to altitude is contradictory to that observed with MSNA, as Hanson and Sander saw progressive and persistent increases in MSNA burst frequencies.  When taken together, these studies suggest that heart and vasculature autonomics are modulated differently  with long term exposure to hypoxia. Also, the limitations in the current non-invasive methods in which to assess heart rate autonomics must be recognized. Rodent models have provided a unique opportunity to study the effects  of  hypoxia on renal sympathetics. Again, separate pre ganglionic nerves from  the RVLM extend to the kidney and adrenal medulla (Appendix C), indicating that differential  recruitment can be anticipated with exposure to sympathetic stimuli, such as hypoxia. In anesthetized artificially  ventilated rats, graded levels of  severe hypoxia was implicated in the increase in direct measures of  adrenal sympathetic nerve activity, measured at the splanchnic nerve and parallel with increases in catecholamine secretion measured in the adrenal venous effluent  (9). This response was dependent on intact carotid sinus nerves and splanchnic nerve. The consequences of  hypoxia on renal sympathetic nerve activity has been extensively studied by Fletcher's group using a 35 day recurrent episodic hypoxia protocol (~7 hours a day; Fj02 = -10%) (33, 34, 36-38, 40-42). Two key findings  suggest a role of  the kidney on the sympathetically mediated increases in blood pressure. First, both renal deinervation and chemical blockade of  renal nerve activity showed no blood pressure change or a lowering of  blood pressure in response to hypoxia, whereas the sham-operated and unhandled rats showed a progressive, sustained increase in resting room air blood pressure (36). Second, sympathetic stimulation of  alpha and beta adrenergic receptors increase the production of  renin. Renin, an enzyme produced by the juxtaglomerular complex (located in the renal cortex of  the kidney), cleaves angiotensinogen, an alpha-2 globulin produced by the liver. The result is Angiotensin I (AngI) which yields Angiotensin II (Angll) via reaction with angiotensin converting enzyme. The ratio of  Angll to AngI represents plasma renin activity (PRA) an indirect measurement of kidney sympathetic activation. In rats, PRA is increases ~4 fold  after  episodic hypoxic exposures (38). Elevations in renal and adrenal sympathetics, indicated directly or indirectly have acute and chronic cardiovascular implications. Activation of  renal sympathetics may play a role in the persistent MSNA observed with hypoxia, and therefore  constrictor action of  vascular tissue. It has been suggested that epinephrine (EPI), released from  the adrenal medulla during hypoxia, may be taken up by post ganglionic nerves and released as a co-transmitter with NE (9) (refer  to Appendix D). Furthermore, Ang II facilitates  NE release through its action on ATi receptors located at terminal branches. Consequently, potentiation of  peripheral sympathetic neurotransmission and end organ response (vasoconstriction) may result. Additionally, increases in Angll, such as those observed with hypoxia increase heart rate and myocardial contractility. Chronic overproduction of  Angll can lead to hypertrophy and/or hyperplasia of  vascular smooth muscle and activation of  vascular trophic factors  (27). Therefore,  the renin-angiotensin system is an important contributor in the elevated blood pressure observed in response to chronic hypoxia and may be implicated in those with dirurnal hypertension associated with OSA. Figure 3. Representative trace for  one subject during the post IH trial. Note that although ventilation, Sa02, and Fj02 all return to baseline values during recovery, MSNA remains elevated. BASELINE HYPOXIC EXPOSURE RECOVERY o U 'S3- •O E -a E W 0 ; 1 £ H f B ^ w O ft. < ^ z > c/3 c-2 - O <_) w 3 „ cn oO o 33 • a. B o •0.5 •1 -1.5 .'60 : 40 20 0 -20 rnmlis rnmRMii no: 100 90 80 TO 60 100 50 0: -50 ^mrnmm mmmm Kj\J\J\f\S\J\f\^ \J\J\J\J\AJ\f\ 10 seconds Abbreviations: arterial oxygen saturation (Sa02), fraction  of  inspired oxygen (FJ02), muscle sympathetic nerve activity (MSNA). Hypoxia and sympathetic drive Hypoxia is detected in the periphery, primarily via the carotid bodies and sensory afferent  transmissions are relayed to the central nervous systems. The central nervous system responds by enhanced sympathetic activity directed to the various organs and vasculature. Abbreviations: nucleus tractus solitarius (NTS), rostral ventral lateral medulla (RVLM) RVLM <ZZZ2> Heart O Kidney O — • Sympathetic control via the rostral ventral lateral medulla. The RVLM is charged with sympathetic control. The presympathetic neurons extending from  the RVLM terminate in separate regions and therefore  differential  recruitment can be anticipated in response to physiological stimuli, such as hypoxia. Figure adapted from  Guyenet, 2000. Abbreviations: rostral ventral lateral medulla (RVLM) Central Chemoreceptor Activation Other Organ Systems Hypoxia and renal sympathetics. The kidney and the adrenal medulla may play a role in the persistent activation of  the sympathetic nervous system during hypoxia. Chronic activation of such pathways has implications on the cardiovascular system and vascular properties. Concepts adapted from  Biesold et al. 1989. Abbreviations: epinephrine (EPI), plasma renin activity (PRA), norepinephrine (NE) REFERENCES 1. Standardization of  Spirometry, 1994 Update. American Thoracic Society. Am J  Respir Crit  Care  Med  152: 1107-1136, 1995. 2. Ainslie PN and Poulin MJ. Respiratory, cerebrovascular and pressor responses to acute hypoxia: dependency on PET(C02). Adv  Exp Med  Biol 551: 243-249, 2004. 3. Ainslie PN and Poulin MJ. Ventilatory, cerebrovascular, and cardiovascular interactions in acute hypoxia: regulation by carbon dioxide. 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