During sleep and with the loss of the "wakefulness" drive to pump and upper airway respiratory muscles, the control of breathing becomes highly dependent upon and vulnerable to reflexive feedback inputs from chemoreceptors and mechanoreceptors. Accordingly, sleep-induced breathing instabilities are common and have a significant prevalence even in the general population. Sleep unmasks a highly sensitive hypocapnic-induced apneic threshold, but we do not know what role this mechanism plays in various types of sleep-disordered breathing, because we do not know its sites of action, its changes in sensitivity in the presence of powerful background influences such as CNS hypoxia, chronic hypocapnia/hypercapnia, changing sleep states, or changing stimuli to breathe which might be specific to sleep. We will use sleeping humans and dogs, the latter with extra corporeal perfusion of isolated carotid chemoreceptors-to quantify the effect of these influences on both the apneic threshold and on the important stabilizing mechanism of short term potentiation of ventilatory output. This dog model with isolation of carotid chemoreceptors will also be used to address the question of central versus peripheral hypoxic effects on periodic breathing in sleep. A second dog model as well as human patients with chronic heart failure will be studied to address the mechanisms of Cheyne-Stokes respiration, with specific emphasis on the effects of the added stimulus to hyperventilation originating from the lungs of the patient in congestive heart failure. Finally, we will use dogs and humans-with and without innervated lungs-to address the role of non-chemical, mechanoreceptor inhibitory feedback effects during sleep on upper airway and pump muscles; a) influences from high frequency low amplitude pressure oscillations in the upper airway; b) the effects of amplitude, timing and duration of normocapnic mechanical ventilation on the resetting of inherent respiratory rhythm and on the "short-term inhibition" of respiratory motor output following cessation of phasic inhibitory sensory input. These latter studies conduced in sleep are important to testing the sensitivity of respiratory control mechanisms to mechanical feedback-a problem which remains relatively unexplored, especially in the human.