Chronic intermittent hypoxia (CIH) is a widely used model for the repetitive bouts of hypoxemia that occur during sleep in sleep apnea patients. During such apneic periods, hypoxia activates chemoreceptors that evoke reflex increases in arterial pressure. In humans with sleep apnea and animals exposed to CIH the repetitive periods of hypoxia during sleep result in tonically increased arterial pressure during waking hours, likely the result of elevated levels of sympathetic nerve activity and an enhanced response to acute hypoxia. The goal of the present project is to investigate the central pathways and mechanisms that underlie this persistent increase in sympathetic nerve activity. It is hypothesized that CIH leads to alterations in ligand gated excitatory and/or inhibitory amino acid receptors in noradrenergic (A2) neurons in the nucleus of the solitary tract (NTS) so that their discharge is increased compared to before CIH. These neurons transmit this enhanced discharge to sympatho-excitatory neuron in the paraventricular nucleus (PVN) of the hypothalamus. PVN neurons receiving the catecholaminergic input include neurons that release corticotropin releasing factor (CRF) as a transmitter. The CRF releasing PVN neurons mediate, at least in part, the enhanced sympathetic discharge observed following CIH via projections to the RVLM and by stimulating corticosterone release. Both in vivo and in vitro approaches will be used and microinjection, electro-physiological and molecular studies are proposed to characterize the synaptic integration of chemoreceptor inputs and the molecular regulation of the neurotransmitter receptors that mediate these integrative processes.
The specific aims are designed to assess: 1) The integration of arterial chemoreceptor inputs within the NTS following CIH; 2) The integration of A2, noradrenergic inputs within the PVN following CIH; and 3) The functional activation of the CRF system within the PVN following CIH.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL066335-04
Application #
6619581
Study Section
Special Emphasis Panel (ZHL1-CSR-H (S1))
Program Officer
Twery, Michael
Project Start
2000-09-30
Project End
2005-08-31
Budget Start
2003-09-01
Budget End
2005-08-31
Support Year
4
Fiscal Year
2003
Total Cost
$252,875
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Pharmacology
Type
Other Domestic Higher Education
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Hinojosa-Laborde, Carmen; Mifflin, Steven W (2005) Sex differences in blood pressure response to intermittent hypoxia in rats. Hypertension 46:1016-21