Chronic exposure to intermittent hypoxia (CIH) is a widely used animal model of the arterial hypoxemia that occurs during sleep apnea. CIH in animals has been shown to result in an increased blood pressure as seen in human sleep apnea patients and this hypertension is dependent upon the sympathetic nervous system (SNS) and angiotensin (Angll). Current explanations for CIH-induced hypertension include arterial chemoreceptor activation providing a driving force for a persistent increase in sympathetic nerve discharge. The nucleus of the solitary tract (NTS) is the primary CNS site of termination of arterial chemoreceptor afferent fibers. The overall hypothesis of this project is that repetitive activation of the arterial chemoreceptors by CIH increases the discharge of and the responsiveness of neurons in the NTS that regulate sympathetic and HPA axis function. The adrenal steroid corticosterone (CORT) has been shown to be increased following acute exposures to hypoxia. CORT has been shown to enhance the pressor effect of centrally administered Angll and Angll within the NTS facilitates synaptic and chemoreflex responses. It is hypothesized that enhanced Angll mediated responses (increased calcium influx) result in enhanced responses to the excitatory transmitter AMPA. As a result, the sensitivity of NTS neurons to arterial chemoreceptor inputs is enhanced which contributes to the elevations in blood pressure, sympathetic nerve discharge and sympathetic reactivity observed after CIH. It is hypothesized that catecholaminergic (A2) and glutamatergic neurons in the caudal NTS are the primary sites where these alterations occur.
Specific Aim 1 : The first goal is to characterize how NTS neurons respond and adapt during exposure to CIH and the role of hypoxia in mediating/modulating responses to chemoreceptor afferent inputs.
Specific Aim 2 : The second goal is to determine the role of the glucocorticoid Type II receptor as a mediator of these adaptive changes in NTS neurons.
Specific Aim 3 : The third goal is to determine the role of angiotensin in the alterations in NTS neurons induced by CIH. The results of these studies will provide new insights into the mechanisms whereby CIH leads to elevated blood pressure, sympathetic nerve discharge and sympathetic reactivity. These factors mediate much of the pathology associated with sleep apnea including hypertension, increased risk of adverse cardiovascular events and insulin resistance. ? ? ?
| Ma, S; Mifflin, S W; Cunningham, J T et al. (2008) Chronic intermittent hypoxia sensitizes acute hypothalamic-pituitary-adrenal stress reactivity and Fos induction in the rat locus coeruleus in response to subsequent immobilization stress. Neuroscience 154:1639-47 |
