The arterial chemoreflex increases breathing and arterial blood pressure during periods of low arterial oxygen (hypoxia) and participates in physiological adaptations and in disease states such as obstructive sleep apnea (OSA). Patients suffering from OSA, and animal models experiencing chronic intermittent hypoxia (CIH), exhibit augmented chemoreflexes, sympathoexcitation and hypertension. Furthermore, enhanced chemoreflex function may contribute to the sympathoexcitation associated with diseases such as heart failure and hypertension. Peripheral carotid body chemoreceptors sense arterial oxygen pressure and send afferent fibers to the caudal nucleus tractus solitarius (nTS) where glutamate is released and binds to ionotropic glutamate receptors. The afferent signal is then integrated within the nTS to produce the final output within the nTS- chemoreflex circuit. nTS output neurons project to the rostral ventrolateral medulla (RVLM) and the hypothalamic paraventricular nucleus (PVN), and both of these brain regions likely contribute to acute and chronic chemoreflex responses. The RVLM contains neurons crucial for basal and reflex control of sympathetic activity and breathing in health and disease. The PVN also contributes to changes in autonomic regulation in a variety of disease states;some of these changes may be due to altered inputs, possibly from the nTS. Previous studies evaluating chemoreflex transmission have focused on second order nTS neurons receiving afferent input and little is known concerning the activity of output neurons from the nTS. These neurons determine the final integrated signal critical to chemoreflex function and thus, discerning the function of these output neurons is essential to understanding the impact of the nTS on cardiorespiratory regulation in health and disease. Within the nTS, reactive oxygen species (ROS), derived primarily from NADPH oxidase, are important signaling molecules. Hypoxia increases production of ROS, and increases in ROS in autonomic regions of the brain have been implicated in enhanced sympathetic activity in hypertension and heart failure. Our central hypothesis is that the intrinsic characteristics, inputs and neurotransmitter receptors present on RVLM- and PVN-projecting nTS neurons determine their response to chemoreceptor activation. Furthermore, the response of these different populations of nTS neurons to hypoxia is dependent on the intensity and duration of the hypoxic stimulus and is influenced by glutamate receptor subtype and the production of ROS in the nTS.
The Specific Aims are: 1) To determine the neuronal characteristics, neurotransmitter/receptor systems and the role of reactive oxygen species in the response to acute hypoxia of RVLM- and PVN- projecting nTS output neurons and 2) To determine the role of RVLM- and PVN-projecting nTS output neurons and reactive oxygen species in the response to chronic intermittent hypoxia and to acute hypoxia following CIH. Complementary results and interpretations will be obtained from whole animal, cellular and molecular experiments.
Obstructive Sleep Apnea (OSA) and many other disease states manifest as unstable breathing and hypertension. The central nervous system has been implicated in these pathophysiological responses, but the central site of action and mechanism are not known. The possible role of reactive oxygen species in the brain also is not known. The brainstem is a vital region which controls blood pressure and breathing. Our studies will determine the relevance of reactive oxygen species in brainstem neurons on their control of blood pressure and breathing. This will be done in a model of OSA with the expectation of understanding potential therapeutic interventions.
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