Shell, Brent
Cunningham, Tom


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Sleep apnea can increase blood pressure. It is not understood what changes in the brain occur while experiences lack of oxygen during sleep apnea that results in high blood pressure both during the day and during the sleeping hours. Our lab uses a model of sleep apnea that exposes rodents to periods of reduced oxygen. We have found that removing a receptor for a specific chemical in the front of the brain prevents the increase of blood pressure during the normal oxygen waking hours. This current study shows that the knockdown of this receptor decreases activity in the rear portions of the brain that directly control blood pressure. Understanding the mechanisms how sleep apnea leads to hypertension is essential for effective treatment of the disease. Purpose (a): The repeated bouts of hypoxia experienced by sufferers of sleep apnea results in persistent blood pressure elevation. This pathophysiological increase in pressure exists in both the hypoxic night phase and the normoxic period. Neurological mechanisms that drive this maladaptive blood pressure increase are not well understood. Our lab has shown that knockdown of the Angiotensin type 1a (At1a) receptor in a forebrain nucleus, the median preoptic nucleus (MnPO), prevents the normoxic blood pressure increase. How the MnPO At1a receptors affect downstream nuclei to maintain normal pressure is not known. In the current study, rats were exposed to chronic intermittent hypoxia (CIH) to simulate the hypoxic effects of sleep apnea. We then examined the activity of downstream nuclei by performing immunohistochemistry for ∆FosB, a marker for neuronal activity. We hypothesize that knockdown of AT1a in the MnPO results in decreased ∆FosB expression in downstream hypertensive nuclei such as the caudal ventrolateral medulla (CVLM), the rostral ventrolateral medulla (RVLM), and the nucleus tractus solitaries (NTS). Methods (b): After exposure to chronic intermittent hypoxia (CIH), rats are sacrificed, perfused with 4% paraformaldehyde, dehydrated with sucrose, and serial sectioned at 40 microns on a cryostat. Sections are split into three groups; one group is used for immunohistochemistry. Sections are processed with primary goat antibody for ∆FosB, a secondary biotinilated anti-goat, and finally visualized using diaminobenzidine. Localization of the NTS, CLVM, and RVLM was performed by double labeling for dopamine-β-hydroxylase (DβH), an enzyme used in the production of catecholamines. DβH was visualized using a CY3 fluorophore. Cell counts utilized at least 3 brain sections per nucleus. Results (c): A significant difference was found between the AT1a knockdown rats and the scramble rats in the subpostremal region of the NTS. This region has neurons that are responsible for processing both baroreceptor and chemoreceptor information. Conclusions (d): The MnPO is connected to this region through the paraventricular nucleus. Decreased MnPO activity could cause a decrease in the quantity of inputs to the hindbrain. These results, coupled with the prevention of the normoxic blood pressure increase, indicate that angiotensin acting through the MnPO is affecting the activity of neurons in the brainstem that are directly controlling blood pressure regulation.


Research Appreciation Day Award Winner - 2014 Cardiovascular Research Institute - 1st Place Graduate Student