Mechanisms and clinical implications of the neuroendocrine response to a novel carbon dioxide stressor in man

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    Maintenance of normal health requires an intact stress system capable of mounting the metabolic, autonomic, behavioural and motor responses required for coping with or avoiding physiological and pathological challenges. The neuroendocrine component of this response principally involves the hypothalamic-pituitary-adrenal (HPA) and sympatho-adrenomedullary (SAM) axes. Impaired regulation of these axes has been implicated in the pathogenesis and expression of numerous disease states, however, it has proved very difficult to reproducibly activate the HPA and SAM axes and no single test exists that can reliably and safely be used to study these systems in man. Carbon dioxide (CO2) is the principal regulator of respiration, acid-base balance and behavioural-state arousal in humans. Paradigms of CO2 inhalation have been used in psychiatric research to investigate panic and anxiety disorders, but evaluation of other components of the stress response to CO2 has not previously been performed. I hypothesised that a single breath of 35% CO2 would be a simple and reliable tool for the evaluation of the stress response in humans. A single breath of four doses of CO2 (5%, 25%, 35% and 50%) was administered to 9 healthy volunteers in a randomised, single blind fashion. Subjective symptoms of anxiety increased in a dose-dependent manner. Inhalation of a single breath of 35% CO2 stimulated significant ACTH (p = 0.006), noradrenaline (p < 0.0001), cortisol (p = 0.02) and prolactin (p = 0.002) release. It also provoked an acute pressor response and an associated bradycardia (p < 0.0001 for both). No significant habituation of psychological, HPA or cardiovascular responses was seen when this dose was repeated after one week (n = 10) or 6 months (n = 5). It was apparent that a single breath of 35% CO2 reliably and safely produced SAM and HPA axis activation and further studies were then undertaken to assess the mechanism by which the observed responses occurred and its potential clinical implications. Administration of naltrexone (an opiate antagonist) to 10 normal volunteers disinhibited the HPA axis (p < 0.0004), whilst administration of metyrapone (a cortisol synthesis inhibitor) significantly reduced baseline cortisol (p < 0.03) levels. However, this alteration in HPA axis activity had no effect on either cardiovascular or psychological responses. Further, in a study of 8 breastfeeding mothers (a state associated with physiological suppression of the HPA axis) suckling significantly reduced plasma cortisol levels compared with control (p = 0.002) and bottle-feeders (p = 0.003). Despite this cortisol, systolic blood pressure (SBP), heart rate and psychological responses to 35% CO2 were not affected
    Original languageEnglish
    QualificationDoctor of Philosophy
    Publication statusUnpublished - 2005


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