Sleep apnea syndrome is prevalent (3-5 percent of the adult population) and associated with significant morbidity including hypertension. The increased blood pressure appears to result from an up-regulation of basal sympathetic nerve activity (SNA). Treatment reverses this up-regulation. We theorize that the up-regulation of SNA results from both short- and long-term sequelae of episodic hypoxemia associated with sleep apnea. The respiratory and cardiovascular systems are coordinated in the maintenance of homeostasis. Respiratory modulation of SNA is an aspect of this coordination. Not only is SNA modulated with the respiratory cycle but also this modulation increases during and following brief periods of hypoxemia. The neural substrate for this coordination is undefined. Recent studies have focused on neuronal interaction between medullary respiratory-modulated and pre-motor sympathetic neurons of the rostral ventrolateral medulla (RVLM). However, neurons in the dorsolateral (dl) pontine Kolliker-Fuse (KF) nucleus are the only brainstem neurons other than the those in the NTS that project to the RVLM and that are activated by hypoxia. We hypothesize that a direct pontomedullary interaction between respiratory-modulated neurons of the KF nucleus and neurons in RVLM contributes to the respiratory modulation of sympathetic activity and that this interaction underlies the enhanced respiratory modulation of sympathetic activity during and following hypoxia. To test this hypothesis, we propose a series of neurophysiologic experiments addressing the following specific aims: 1) to determine if inhibition of dl pontine activity blocks the transient and sustained increases in respiratory modulation of SNA during and following hypoxia, 2) to determine if activation of dl pons enhances respiratory modulation of SNA, and 3) to determine if respiratory-modulated KF neurons project to and excite RVLM neurons and if these KF neurons are activated during and after hypoxia. We will investigate the neural substrate controlling respiration and blood pressure, the transient and sustained consequences of brief hypoxemia on this control, and the modulation of this control by morbidity, i.e., the development of hypertension. We propose experiments in normo- and hypertensive rats as well as in cats to evaluate the dl pontine influence on SNA, the changes in this influence with transient hypoxemia and hypertension. These proposed studies examine the mechanism of up-regulation of sympathetic nerve activity that is associated with sleep apnea.
