It is not known if central reactive oxygen species (ROS) generation plays a role in the sustained sympathoexcitation independent of, or in association with, peripheral chemoreceptor activation. One candidate mechanism is the ROS-nitric oxide (NO) interaction in the brain. The sympathoinhibitory role of central NO is well established and it is plausible that ROS generated during hypoxia scavenges NO centrally resulting in increased central sympathetic outflow. Acute intermittent hypoxia (IH) causes a sustained increase in muscle sympathetic nerve activity (MSNA) and resets arterial baroreflex (ABR) function. However, it remains unknown if this alteration in ABR function is prevented and/or reversed by using antioxidant therapy. Furthermore, whether an antioxidant that crosses the blood brain barrier (BBB) is more sympathoinhibitory than the antioxidant acting only at the peripheral chemoreceptors is unknown. To explore this potential 'communicative'role of ROS, we hypothesize that the IH induced generation of ROS increases central sympathetic outflow and resets the operating point (OP) of the arterial baroreflex control of MSNA to enable a sustained increase in MSNA. We previously demonstrated that IH for 20 min leads to a sustained increase in MSNA for at least 180 min. Our Sleep Consultant Faculty has identified two subgroups of OSA patients using an innovative clinical index of continuous positive airway pressure (CPAP) treatment success. We have recently noted that pretreatment with N-acetylcysteine (NAC) prevents the increase in IH induced increase in MSNA. Because the anti-oxidant N-acetyl cysteine (NAC) is lipid soluble and reduces oxidative stress peripherally and centrally, it is difficult to identify whether NAC's sympathoinhibitory effect is due to its action in the central nervous system (CNS) or at the peripheral chemoreceptors, alone. In contrast ascorbic acid (AA) is a water-soluble antioxidant which does not cross the BBB effectively. Hence, in this set of proposed experiments, we will compare the central and peripheral effects of NAC to that of the peripheral effects of AA in reducing acute and chronic IH induced sympathoexcitation. As the incidence and severity of OSA peaks in middle aged adults (45-64 years), we propose to use our novel two-antioxidant protocol with differential BBB penetrability in middle-aged successfully and unsuccessfully treated OSA patients and compare the response measures with age-matched middle-aged healthy adults. We anticipate that the findings of this set of experiments will identify the role of central ROS generation in causing the sympathoexcitation associated with OSA.
This investigation will explore the role of centrally and peripherally generated reactive oxygen species in mediating transient and sustained sympathoexcitation in middle-aged healthy and age-matched continuous positive airway pressure treated obstructive sleep apnea patients.
|Jouett, Noah P; Moralez, Gilbert; White, Daniel W et al. (2016) N-Acetylcysteine reduces hyperacute intermittent hypoxia-induced sympathoexcitation in human subjects. Exp Physiol 101:387-96|
|White, Daniel W; Shoemaker, J Kevin; Raven, Peter B (2015) Methods and considerations for the analysis and standardization of assessing muscle sympathetic nerve activity in humans. Auton Neurosci 193:12-21|
|Raven, Peter B; Chapleau, Mark W (2014) Blood pressure regulation XI: overview and future research directions. Eur J Appl Physiol 114:579-86|
|Fadel, Paul J; Raven, Peter B (2012) Human investigations into the arterial and cardiopulmonary baroreflexes during exercise. Exp Physiol 97:39-50|