Grant: Discovery Grants Program - Individual

Anyone who has ever held their breath will have felt an overwhelming urge to resume breathing and a coincident rise in heart contractions. This response is governed by chemoreflexes arising from specialized carbon dioxide/acid sensors in the brainstem and arteries that activate breathing and the circulation (via the sympathetic nervous system) in ways that counteract the acidifying and blood pressure lowering effects of carbon dioxide. Often, in environments (e.g. poorly ventilated areas), activities (e.g. exercise) and conditions (e.g. sleep) that challenge carbon dioxide removal, central and peripheral chemoreflexes are engaged simultaneously but their relative contributions to breathing and circulatory responses have yet to be established. A source of controversy is whether they compete with each other and with other reflexes that are stimulated by breathing and blood pressure changes. The objective of my research program is to determine whether central and peripheral chemoreflexes interact with each other in the control of breathing and with other sympathetic nervous system sensors that regulate the resistance to flow within the small vessels of skeletal muscle when pH falls. My research program will explore the hypothesis that central and peripheral chemoreflexes do not interact in the control of breathing (their drives are additive) but their ability to reflexively raise sympathetic outflow is modulated by other respiratory and cardiovascular reflexes. My approach employs techniques to study the impact of alterations in tissue oxygen and carbon dioxide (stimulus) pressures on the respiratory, sympathetic and cardiovascular systems (response) in humans. I apply breath-by-breath measures of flow, volume and gas exchange to quantify ventilation and to measure end-tidal gas pressures. With this method, I can precisely alter blood gas pressures, and thus known input to central and peripheral chemoreceptors, by manipulating inspired gas concentrations in unique ways. To capture the respiratory and sympathetic output in response to chemoreceptor stimulation, I assess ventilation in concert with the technique of microneurography to directly record the firing discharge of vasoconstrictive sympathetic nerves innervating muscle vasculature. My research will develop new models of respiratory and sympathetic control via the chemoreflexes and provide a high-quality training environment for trainees to develop desirable research skills in human cardiorespiratory investigation. Chemoreflexes are increasingly recognized in the pathophysiology of conditions that impact the respiratory (sleep apnea; lung disease) and cardiovascular systems (heart failure, hypertension); as a mechanism of disordered breathing and source of excess sympathetic nervous system activation. Chemoreflex control models will impact therapies and trials designed to intervene at the central and peripheral chemoreceptors to stabilize breathing or inhibit their sympathetic output.