MODULATION OF BREATHING BY UPPER AIRWAY CHEMORECEPTORS

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Apnea in the pediatric and adult age groups still remains a phenomenon that is poorly understood. However, recent evidence suggests that one important determinant factor in the generation of apnea is the activity level of peripheral respiratory afferents. We propose to study the interaction between upper airway chemoreceptive afferents and the neonatal respiratory and cardiovascular control systems as a function of sleep state and age. Because anesthesia and surgical trauma may alter cardio-respiratory responsiveness, all proposed studies will take place in unanesthetized, chronically instrumented piglets. Studies will center on the effects of stimulating superior laryngeal afferents. Stimulation will be used for two purposes: 1) as a specific challenge to neonatal breathing which demands a specific response to clear the airway and resume breathing, and 2) as a means for depressing the respiratory system in a controlled fashion in order to examine the synergistic effects between neuromodulators and upper airway afferents. Our preliminary results have shown that electrical stimulation of the superior laryngeal nerve in unanesthetized neonatal piglets leads to a profound depression of breathing, hypoxia and hypercapnia which lasts throughout the duration of stimulation (1 hour) and is not associated with discomfort to the animal. We propose to examine this phenomenon by measuring ventilation (barometric method), cardiac output and organ blood flow distribution (microspheres), heart rate and heart rate variability, blood pressure (chronic cannula), O2 consumption (closed system) and upper and lower airway resistance during SLN stimulation at various ages and sleep states in early life. Brainstem respiratory responsiveness will be altered through intracisternal injection of endorphins and GABA agonists and antagonists. Chemoreceptor effects will be discerned by changing ambient O2 or CO2 tension, venous injection of small amounts of NaCN and peripheral chemodenervation. We believe that this work will generate new and important data for the understanding of neonatal apnea syndromes such as sleep apnea (unexplained apnea) and upper airway obstruction that may lead to cardiorespiratory collapse. The anticipated results of this work will very likely identify those areas of the respiratory system which are of particular importance in sustaining breathing during challenge and so may ultimately lead to pharmacologic targeting and better therapeutic modalities in the treatment of those infants subject to bouts of life threatening apneas.