Exposure to chronic hypoxia (CH) leads to ventilatory acclimatisation to hypoxia (VAH) which is a time-dependent increase in breathing. This study examined the role of the GABAA receptor in establishing VAH. Rats were exposed to CH or control (normoxic) conditions for 10 days during which the GABAA receptor antagonist, bicuculline, was infused systemically or directly into the nucleus of the solitary tract (NTS). Acute breathing trials were then performed to measure resting ventilation and ventilatory chemoreflexes. Systemic administration of bicuculline caused reductions in breathing during acute hypoxia and acute hypercapnia in the control but not the CH animals. Continuous infusion of bicuculline in to the NTS caused a reduction in the acute hypoxic ventilatory response in animals exposed to CH but not in the control animals. The results indicate that exposure to CH alters the GABAA-mediated regulation of acute ventilatory chemoreflexes both in the NTS and elsewhere in the brain.

No description available.

Notre travail de thèse avait pour buts d’explorer les mécanismes de contrôle de la fonction respiratoire au cours de l’exercice incrémentiel maximal mais également de corréler les évènements biochimiques associés à l’exercice progressif aux modifications de l’électromyogramme des muscles participant à l’effort. Les résultats de nos trois études ont montré : 1) que la baisse de PO2, intervenant pendant les premiers paliers d’un exercice incrémentiel maximal, était bien dépendante d’une défaillance de la commande centrale de la réponse ventilatoire. 2) que le pattern ventilatoire durant la période située entre le seuil ventilatoire (VTh) et le 2ème seuil (RCP) lors d’un exercice incrémentiel, pouvait évoluer selon deux modalités différentes, l’une caractérisée essentiellement par une augmentation de VT (un tiers des sujets) et l’autre déterminée majoritairement par une augmentation de FR. L’hypothèse d’une différence interindividuelle du gain du réflexe de Hering-Breuer peut être évoquée pour expliquer ces différents modes ventilatoires pendant l’exercice ; 3) qu’il est mesuré une augmentation de la concentration plasmatique de l’IMA (marqueur du stress oxydatif), corrélée à la consommation de RAA (antioxydant endogène), durant la phase la plus intense de l’exercice incrémentiel. L’adaptation de la commande motrice via le mécanisme d’épargne musculaire (« muscle wisdom ») n’intervient que chez les sujets qui développent un stress oxydatif. Ainsi, la variabilité interindividuelle mesurée dans l’amplitude du stress oxydatif, à niveau d’exercice comparable, affecte la capacité des sujets à lutter contre la fatigue musculaire. / The aim of our PhD work was to explore, in healthy humans, the control mechanisms of the respiratory function during a maximal incremental exercise and also to correlate the changes in the motor control of working muscles to the changes in exercise-induced blood signals. The results of our three studies showed:1) The occurrence of a PO2 fall during the first steps of the incremental exercise, associated with a modest PCO2 increase, strongly suggests a non-adaptation of the central command to the oxygen demand and CO2 washout;2) Two opposite changes in the ventilatory pattern were observed between the ventilatory threshold (VTh) and the respiratory compensation point (RCP); one third of the subjects tends to recruit predominantly VT and the others the breathing frequency. The hypothesis of an inter-individual difference in the strength of the Hering-Breuer reflex seems to be the more consistent explanation. 3) The plasma concentration of IMA, a marker of the oxidative stress, increased at the highest levels of incremental exercise and was correlated to the consumption of endogenous antioxidant (RAA). Because we observed that the adaptive motor response to cycling (leftward shift of the EMG spectrum) closely depends on the importance of the oxidative stress response, we hypothesized that all the healthy subjects do not have the same chances to be protected against muscle fatigue.

This study investigated two hypotheses. First, that chronic cocaine treatment would mimic the changes in breathing that are associated with ventilatory acclimatisation to chronic hypoxia (VAH). Second, that pre-treatment with a hypoxic stressor would bring about cross-sensitisation to cocaine. To address the first hypothesis, rats were exposed to either chronically hypoxic or chronically normoxic conditions and treated with either cocaine or saline for a 14 day period. Following this period, acute breathing trials were performed to measure resting ventilation and ventilatory chemoreflexes. The results demonstrated that chronic cocaine treatment did not induce the changes in breathing associated with VAH. To address the second hypothesis rats were exposed to a hypoxic stressor for 10 days (either intermittent hypoxia or chronic hypoxia) after which cocaine sensitisation was measured via locomotor sensitisation trials. The results demonstrated that cross-sensitisation between a hypoxic stress and cocaine was observed for intermittent but not chronic hypoxia.

This study investigated two hypotheses. First, that chronic cocaine treatment would mimic the changes in breathing that are associated with ventilatory acclimatisation to chronic hypoxia (VAH). Second, that pre-treatment with a hypoxic stressor would bring about cross-sensitisation to cocaine. To address the first hypothesis, rats were exposed to either chronically hypoxic or chronically normoxic conditions and treated with either cocaine or saline for a 14 day period. Following this period, acute breathing trials were performed to measure resting ventilation and ventilatory chemoreflexes. The results demonstrated that chronic cocaine treatment did not induce the changes in breathing associated with VAH. To address the second hypothesis rats were exposed to a hypoxic stressor for 10 days (either intermittent hypoxia or chronic hypoxia) after which cocaine sensitisation was measured via locomotor sensitisation trials. The results demonstrated that cross-sensitisation between a hypoxic stress and cocaine was observed for intermittent but not chronic hypoxia.

Methadone is a long acting mu-opioid and is the most effective treatment for heroin addiction. However, opioids depress respiration and methadone maintenance treatment (MMT) patients have a higher mortality rate than the general population. Teichtahl et al conducted a pilot study and found 6 out of 10 MMT patients had central sleep apnea (CSA). But no definite conclusions were made regarding the prevalence and possible pathogenesis of CSA in the patients due to the small sample size and lack of blood toxicology data. The present project aims to confirm the preliminary results and further quantify the sleep disordered breathing (SDB) in stable MMT patients and to delineate the pathogenesis involved. (For complete abstract open document)

No description available.

Multicellular organisms typically depend on O₂ for energy production to maintain normal cellular function, and even brief periods of O₂ deprivation may have fatal consequences. The aqueous environment is prone to changes in ambient water O₂ tension (PO₂) and thus the ability of fish to sense changes in water PO₂ and to elicit appropriate physiological responses is essential for their survival. Studies on fish O₂ chemoreception have identified neuroepithelial cells (NECs), which are characterized as having dense-cored vesicles containing serotonin (5-HT), as peripheral O₂ chemoreceptors. Upon exposure to hypoxia, isolated and cultured NECs in vitro depolarize, likely resulting in neurotransmitter release. However, to date there is no evidence that NECs are activated by hypoxia in vivo to initiate physiological responses such as the hypoxic ventilatory response (HVR), which is the focus of this thesis. Initial findings demonstrated that larval zebrafish fine-tune the HVR as early as 4 days post fertilization (dpf) and by 7 dpf, the HVR aids in O₂ uptake under hypoxic conditions. In addition, the HVR is multiphasic, with an initiation phase followed by a decline phase that gradually stabilizes above normoxic baseline values (Chapter 2). In the absence of tools to probe the hypoxia sensitivity of NECs in vivo, research focused on Merkel-like cells (MLCs), a newly proposed O₂ chemoreceptor in larval zebrafish. Using in vivo calcium imaging it was shown that MLCs are stimulated by hypoxia. Data suggest that MLCs are responsible for the initiation phase of the HVR, while peripheral sensory neurons (PSNs)/peripheral sensory ganglia (PSG) that innervate MLCs play a more important role in reducing ventilation during the decline phase of the HVR (Chapter 4). Attempts at identifying the putative neurotransmitter(s) involved in the O₂ signal transduction pathway revealed that adrenaline (AD), serotonin (5-HT), and dopamine (DA) are probable candidates (Chapter 4), though the presence of AD and DA within MLCs is yet to be confirmed. In addition, 5-HT likely plays a role in the central nervous system (CNS), integrating peripheral signals resulting in the final HVR (Chapter 3). Taken together, this thesis provides the first evidence of putative O₂ chemoreceptors responding to hypoxia in vivo and thus significantly advances models for O₂ signal transduction in larval zebrafish.

Background: Although several reports have shown an adverse cardiovascular and metabolic risk profile associated with childhood obesity, few reports have examined the effects of childhood obesity on pulmonary function. Objective: The purpose of this study was to examine the influence of obesity on pulmonary function in Navajo and Hopi children. Methods: Subjects included 256 (110 males, 16 females) Hopi children 6-12 years of age and 557 (274 males, 283 females) Navajo children 6-12 years of age (N=813). The body mass index was used to classify subjects as normal weight, overweight, or obese on the basis of international reference values. Forced vital capacity (FVC), forced expired volume in one second (FEVl), FEV1% (FEV1 to FVC ratio; FEV1/FVC), and forced expiratory flow between 25%-75% of vital capacity (FEF25-75) were determined according to the American Thoracic Society recommendations. Results: Approximately 26% of Navajo and Hopi children were defined as overweight (26.0% of boys and 25.6% of girls) and an additional 16% (14.6% of boys and 17.7% of girls) were defined as obese. In general, the patterns showed an increase in pulmonary function between normal weight and over-weight children and a decrease in pulmonary function of obese children. Significant differences among groups existed for FEV1% and FEF25-75 in boys and FVC and FEV1 in girls. Conclusions: The results indicate the pulmonary consequences of obesity in children and provide further evidence of the adverse consequences, of pediatric obesity among Native Americans.

BACKGROUND: Previous research has shown that the ventilatory threshold (VT) correlates highly with onset of lactate accumulation and maximal steady-state exercise (MSS) level. Also, studies have shown the VT is useful in prescribing exercise for cardiac patients in that it gives an exercise intensity at which the patient is metabolically stable. METHODS: The purpose of this study was to determine if a MSS response could be achieved at an exercise intensity corresponding to the VT for patients with CAD. A group of 31 patients with CAD performed a maximal effort treadmill exercise test in which respiratory gas exchange was measured. The VT was determined using the V-slope method of computer regression analysis of the plot of carbon dioxide production versus oxygen consumption. Subjects then performed a constant load treadmill test a speed and grade that corresponded to the VT. Heart rate (HR), systolic blood pressure (SBP), and rating of perceived exertion (RPE) evaluated for steady-state responses. If subjects showed a steady-state response in two of these three parameters they were scored as having achieved a maximal steady-state (MSS+) response; those not meeting this standard were scored as failing to achieve maximal steady-state (MSS-) response. Subjects were analyzed as an entire group (N=31), as well as analyzed in subsets according to history of myocardial infarction (MI+, N=20; MI-, N=11) and administration of beta-blocker medications (BB+, N=16; BB-, N=15). RESULTS: Overall, subjects demonstrated significantly more MSS+ responses than MSS- responses (80% Vs 20%, P<0.05). Analysis of the subgroup data showed that it was the patient s with a history of MI (MI+ =85%, P<0.05) and those not receiving beta-blocker medications (BB- = 93%, P<0.05) who had significantly greater proportions of subject achieving MSS+ responses in the fixed load exercise condition. Conversely patient in the MI- (73 %, P < 0.05) and BB (69% P < 0.05) groups showed no significant differences in the number of MSS+ and MSS- responses. CONCLUSIONS: The VT, as measured during ramp exercise testing on the treadmill, provided a basis for establishing a maximal steady-state load in terms of cardiovascular and perceptual variables for 80% of the patients in the CAD study group. The measurements of HR, SBP, and RPE are easily obtained in a clinical setting and thus enable the VT to be used in bringing about a more efficacious exercise prescription. The validity of this method may be questioned, however, for patient with out a history of MI and for those receiving beta-blocker medications. / Master of Science