scholarly journals AT1a Receptor Knockdown in the Median Preoptic Nucleus Attenuates the Sustained Component of Hypertension Resulting from Chronic Intermittent Hypoxia

2013 ◽  
Vol 27 (S1) ◽  
Author(s):  
Brent Shell ◽  
Joel Little ◽  
Tom Cunningham
Keyword(s):  
Intermittent Hypoxia ◽  
Chronic Intermittent Hypoxia ◽  
Preoptic Nucleus ◽  
Median Preoptic Nucleus ◽  
At1a Receptor

scholarly journals Angiotensin type 1a receptors in the median preoptic nucleus support intermittent hypoxia-induced hypertension

2019 ◽  
Vol 316 (5) ◽  
pp. R651-R665 ◽  
Author(s):  
Brent Shell ◽  
George E. Farmer ◽  
T. Prashant Nedungadi ◽  
Lei A. Wang ◽  
Alexandria B. Marciante ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Intermittent Hypoxia ◽  
Renin Angiotensin System ◽  
Receptor Expression ◽  
Male Rats ◽  
Ventrolateral Medulla ◽  
Preoptic Nucleus ◽  
Median Preoptic Nucleus ◽  
At1a Receptor ◽  
Angiotensin Type

Chronic intermittent hypoxia (CIH) is a model of the hypoxemia from sleep apnea that causes a sustained increase in blood pressure. Inhibition of the central renin-angiotensin system or FosB in the median preoptic nucleus (MnPO) prevents the sustained hypertensive response to CIH. We tested the hypothesis that angiotensin type 1a (AT1a) receptors in the MnPO, which are upregulated by CIH, contribute to this hypertension. In preliminary experiments, retrograde tract tracing studies showed AT1a receptor expression in MnPO neurons projecting to the paraventricular nucleus. Adult male rats were exposed to 7 days of intermittent hypoxia (cycling between 21% and 10% O2 every 6 min, 8 h/day during light phase). Seven days of CIH was associated with a FosB-dependent increase in AT1a receptor mRNA without changes in the permeability of the blood-brain barrier in the MnPO. Separate groups of rats were injected in the MnPO with an adeno-associated virus containing short hairpin (sh)RNA against AT1a receptors to test their role in intermittent hypoxia hypertension. Injections of shRNA against AT1a in MnPO blocked the increase in mRNA associated with CIH, prevented the sustained component of the hypertension during normoxia, and reduced circulating advanced oxidation protein products, an indicator of oxidative stress. Rats injected with shRNA against AT1a and exposed to CIH had less FosB staining in MnPO and the rostral ventrolateral medulla after intermittent hypoxia than rats injected with the control vector that were exposed to CIH. Our results indicate AT1a receptors in the MnPO contribute to the sustained blood pressure increase to intermittent hypoxia.

Chronic Intermittent Hypoxia Alters the Chloride Gradient in Median Preoptic Nucleus (MnPO) Neurons of Rats

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
George E Farmer ◽  
Joel T Little ◽  
Martha E. Bachelor ◽  
Nataliya Rybalchenko ◽  
Joseph Yuan ◽  
...  
Keyword(s):  
Intermittent Hypoxia ◽  
Chronic Intermittent Hypoxia ◽  
Preoptic Nucleus ◽  
Median Preoptic Nucleus

scholarly journals Role of angiotensin-converting enzyme 1 within the median preoptic nucleus following chronic intermittent hypoxia

2017 ◽  
Vol 312 (2) ◽  
pp. R245-R252 ◽  
Author(s):  
Katelynn Faulk ◽  
Brent Shell ◽  
T. Prashant Nedungadi ◽  
J. Thomas Cunningham
Keyword(s):  
Blood Pressure ◽  
Sleep Apnea ◽  
Angiotensin Converting Enzyme ◽  
Intermittent Hypoxia ◽  
Chronic Intermittent Hypoxia ◽  
Converting Enzyme ◽  
Preoptic Nucleus ◽  
Median Preoptic Nucleus ◽  
Obstructive Sleep

Sustained hypertension is an important consequence of obstructive sleep apnea. An animal model of the hypoxemia associated with sleep apnea, chronic intermittent hypoxia (CIH), produces increased sympathetic nerve activity (SNA) and sustained increases in blood pressure. Many mechanisms have been implicated in the hypertension associated with CIH, including the role of ΔFosB within the median preoptic nucleus (MnPO). Also, the renin-angiotensin system (RAS) has been associated with CIH hypertension. We conducted experiments to determine the possible association of FosB/ΔFosB with a RAS component, angiotensin-converting enzyme 1 (ACE1), within the MnPO following 7 days of CIH. Retrograde tract tracing from the paraventricular nucleus (PVN), a downstream region of the MnPO, was used to establish a potential pathway for FosB/ΔFosB activation of MnPO ACE1 neurons. After CIH, ACE1 cells with FosB/ΔFosB expression increased colocalization with a retrograde tracer that was injected unilaterally within the PVN. Also, Western blot examination showed ACE1 protein expression increasing within the MnPO following CIH. Chromatin immunoprecipitation (ChIP) assays demonstrated an increase in FosB/ΔFosB association with the ACE1 gene within the MnPO following CIH. FosB/ΔFosB may transcriptionally target ACE1 within the MnPO following CIH to affect the downstream PVN region, which may influence SNA and blood pressure.

scholarly journals AT1a dependent GABAA inhibition in the MnPO following chronic intermittent hypoxia

2021 ◽  
Author(s):  
George E. Farmer ◽  
Joel T. Little ◽  
Alexandria B. Marciante ◽  
J. Thomas Cunningham
Keyword(s):  
Intermittent Hypoxia ◽  
Receptor Expression ◽  
Chronic Intermittent Hypoxia ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Spontaneous Action ◽  
Potential Activity ◽  
At1a Receptor

Chronic intermittent hypoxia (CIH) is associated with diurnal hypertension, increased sympathetic nerve activity (SNA), and increases in circulating angiotensin II (ANG II). In rats, CIH increases angiotensin type 1 (AT1a) receptor expression in the median preoptic nucleus (MnPO), and pharmacological blockade or viral knockdown of this receptor prevents CIH dependent increases in diurnal blood pressure. The current study investigates the role of AT1a receptor in modulating the activity of MnPO neurons following 7 days of CIH. Male Sprague-Dawley rats received MnPO injections of an adeno-associated virus with a shRNA against the AT1a receptor or a scrambled control. Rats were then exposed to CIH 8 h a day for 7 days. In vitro loose patch recordings of spontaneous action potential activity were made from labeled MnPO neurons in response to brief focal application of ANG II or the GABAA receptor agonist muscimol. Additionally, MnPO KCC2 protein expression was assessed using Western blot. CIH impaired the duration but not the magnitude of ANG II mediated excitation in the MnPO. Both CIH and AT1a knockdown also impaired GABAA mediated inhibition and CIH with AT1a knockdown produced GABAA mediated excitation. Recordings using the ratiometric Cl- indicator ClopHensorN showed CIH was associated with Cl- efflux in MnPO neurons that was associated with decreased KCC2 phosphorylation. The combination of CIH and AT1a knockdown attenuated reduced KCC2 phosphorylation seen with CIH alone. The current study shows that CIH, through the activity of AT1a receptors, can impair GABAA mediated inhibition in the MnPO contributing sustained hypertension.

scholarly journals Chronic intermittent hypoxia increases blood pressure and expression of FosB/ΔFosB in central autonomic regions

2011 ◽  
Vol 301 (1) ◽  
pp. R131-R139 ◽  
Author(s):  
W. David Knight ◽  
Joel T. Little ◽  
Flavia R. Carreno ◽  
Glenn M. Toney ◽  
Steven W. Mifflin ◽  
...  
Keyword(s):  
Intermittent Hypoxia ◽  
Renin Angiotensin System ◽  
Brain Regions ◽  
Ventrolateral Medulla ◽  
Chronic Intermittent Hypoxia ◽  
Preoptic Nucleus ◽  
Sprague Dawley ◽  
Angiotensin System ◽  
Sprague Dawley Rats ◽  
Obstructive Sleep

Chronic intermittent hypoxia (CIH) models repetitive bouts of arterial hypoxemia that occur in humans suffering from obstructive sleep apnea. CIH has been linked to persistent activation of arterial chemoreceptors and the renin-angiotensin system, which have been linked to chronic elevations of sympathetic nerve activity (SNA) and mean arterial pressure (MAP). Because Fos and FosB are transcription factors involved in activator protein (AP)-1 driven central nervous system neuronal adaptations, this study determined if CIH causes increased Fos or FosB staining in brain regions that regulate SNA and autonomic function. Male Sprague Dawley rats were instrumented with telemetry transmitters for continuous recording of MAP and heart rate (HR). Rats were exposed to continuous normoxia (CON) or to CIH for 8 h/day for 7 days. CIH increased MAP by 7–10 mmHg without persistently affecting HR. A separate group of rats was killed 1 day after 7 days of CIH for immunohistochemistry. CIH did not increase Fos staining in any brain region examined. Staining for FosB/ΔFosB was increased in the organum vasculosum of the lamina terminalis (CON: 9 ± 1; CIH: 34 ± 3 cells/section), subfornical organ (CON: 7 ± 2; CIH: 31 ± 3), median preoptic nucleus (CON 15 ± 1; CIH: 38 ± 3), nucleus of the solitary tract (CON: 9 ± 2; CIH: 28 ± 4), A5 (CON: 3 ± 1; CIH: 10 ± 1), and rostral ventrolateral medulla (CON: 5 ± 1; CIH: 17 ± 2). In the paraventricular nucleus, FosB/ΔFosB staining was located mainly in the dorsal and medial parvocellular subnuclei. CIH did not increase FosB/ΔFosB staining in caudal ventrolateral medulla or supraoptic nucleus. These data indicate that CIH induces an increase in FosB/ΔFosB in autonomic nuclei and suggest that AP-1 transcriptional regulation may contribute to stable adaptive changes that support chronically elevated SNA.

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