HYPERTENSION CAUSED BY SLEEP DISORDER BREATHING--NEURAL MECHANISMS

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Our overall goal is to determine the mechanism whereby sleep disordered breathing (apnea/hypopnea and high upper airway resistance) causes sustained daytime hypertension. We propose that sensitization of the carotid chemoreflex by intermittent asphyxia during sleep is the principal link between sleep disordered breathing and daytime hypertension. Sensitization refers to a time-dependent increase in efferent output for the same level of stimulus. Our specific aims will be pursued in complementary human and animal models. Human studies: First, we will determine the acute effects of asphyxia, high upper airway resistance and arousal on the peripheral circulation during sleep using direct intraneural recordings of muscle sympathetic nerve activity. Secondly, we will determine whether exposure to intermittent asphyxia causes sensitization of chemoreflex control of muscle sympathetic nerve activity and arterial pressure. Finally, we will determine whether sleep disordered breathing causes sensitization of chemoreflex regulation of sympathetic outflow and augmented neurogenic vasoconstriction. We will determine the proportion of hypertension in a working population attributable to sleep disordered breathing by eliminating apnea/hypopnea/snoring with nasal continuous positive airway pressure. Animal studies: In anesthetized dogs, the critical role of the carotid chemoreceptor in the neurocirculatory sensitization to intermittent asphyxia will be demonstrated by recording single unit chemoreceptor afferent activity in the carotid sinus nerve and multiunit efferent activity in the renal and adrenal nerves. In unanesthetized dogs with isolated perfusion of the carotid sinus we will determine whether chemoreflex sensitization occurs in the absence of systemic asphyxia. In unanesthetized dogs, we will evaluate the role of chemoreflex-induced epinephrine secretion in augmenting neurogenic vasoconstriction. Our experiments will define the link between sleep disordered breathing and hypertension. This definition will, in turn, lead to a more rational approach to therapy and identify another category of hypertension with a known pathogenesis.