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 Caspase lesions of PVN-projecting MnPO neurons block the sustained component of CIH-induced hypertension in adult male rats

2020 ◽  
Vol 318 (1) ◽  
pp. H34-H48
Author(s):  
Alexandria B. Marciante ◽  
Lei A. Wang ◽  
Joel T. Little ◽  
J. Thomas Cunningham
Keyword(s):  
Blood Pressure ◽  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Intermittent Hypoxia ◽  
Chronic Intermittent Hypoxia ◽  
Chronic Hypertension ◽  
Pressure Regulation ◽  
Neurogenic Hypertension ◽  
Obstructive Sleep ◽  
Induced Hypertension

Obstructive sleep apnea is characterized by interrupted breathing that leads to cardiovascular sequelae including chronic hypertension that can persist into the waking hours. Chronic intermittent hypoxia (CIH), which models the hypoxemia associated with sleep apnea, is sufficient to cause a sustained increase in blood pressure that involves the central nervous system. The median preoptic nucleus (MnPO) is an integrative forebrain region that contributes to blood pressure regulation and neurogenic hypertension. The MnPO projects to the paraventricular nucleus (PVN), a preautonomic region. We hypothesized that pathway-specific lesions of the projection from the MnPO to the PVN would attenuate the sustained component of chronic intermittent hypoxia-induced hypertension. Adult male Sprague-Dawley rats (250–300 g) were anesthetized with isoflurane and stereotaxically injected bilaterally in the PVN with a retrograde Cre-containing adeno-associated virus (AAV; AAV9.CMV.HI.eGFP-Cre.WPRE.SV40) and injected in the MnPO with caspase-3 (AAV5-flex-taCasp3-TEVp) or control virus (AAV5-hSyn-DIO-mCherry). Three weeks after the injections the rats were exposed to a 7-day intermittent hypoxia protocol. During chronic intermittent hypoxia, controls developed a diurnal hypertension that was blunted in rats with caspase lesions. Brain tissue processed for FosB immunohistochemistry showed decreased staining with caspase-induced lesions of MnPO and downstream autonomic-regulating nuclei. Chronic intermittent hypoxia significantly increased plasma levels of advanced oxidative protein products in controls, but this increase was blocked in caspase-lesioned rats. The results indicate that PVN-projecting MnPO neurons play a significant role in blood pressure regulation in the development of persistent chronic intermittent hypoxia hypertension. NEW & NOTEWORTHY Chronic intermittent hypoxia associated with obstructive sleep apnea increases oxidative stress and leads to chronic hypertension. Sustained hypertension may be mediated by angiotensin II-induced neural plasticity of excitatory median preoptic neurons in the forebrain that project to the paraventricular nucleus of the hypothalamus. Selective caspase lesions of these neurons interrupt the drive for sustained hypertension and cause a reduction in circulating oxidative protein products. This indicates that a functional connection between the forebrain and hypothalamus is necessary to drive diurnal hypertension associated with intermittent hypoxia. These results provide new information about central mechanisms that may contribute to neurogenic hypertension.

scholarly journals Intermittent hypoxia in utero damages postnatal growth and cardiovascular function in rats

2018 ◽  
Vol 124 (4) ◽  
pp. 821-830 ◽  
Author(s):  
Ling Chen ◽  
Zahra Heidari Zadi ◽  
Jin Zhang ◽  
Steven M. Scharf ◽  
Eung-Kwon Pae
Keyword(s):  
Blood Pressure ◽  
Obstructive Sleep Apnea ◽  
Body Weight ◽  
Sleep Apnea ◽  
Intermittent Hypoxia ◽  
Cardiovascular Function ◽  
Left Ventricular ◽  
Chronic Intermittent Hypoxia ◽  
Tibial Length ◽  
Obstructive Sleep

Obstructive sleep apnea (OSA) is common in pregnancy and may compromise fetal and even postnatal development. We developed an animal model to determine if maternal OSA could have lasting effects in offspring. Pregnant Sprague-Dawley rats were exposed to reduced ambient O2 from 21 to 4–5%, approximately once per minute [chronic intermittent hypoxia (CIH)] for 8 h/day during gestation days 3–19. Similarly handled animals exposed to ambient air served as controls (HC). Offspring were studied for body growth and cardiovascular function for 8 postnatal weeks. Compared with HC, prenatal CIH led to growth restriction, indicated by smaller body weight and tibial length, and higher arterial blood pressure in both male and female offspring. Compared with same-sex HC, CIH males showed abdominal obesity (greater ratio of abdominal fat weight to body weight or tibial length), left ventricular (LV) hypertrophy (greater heart weight-to-tibial length ratio and LV posterior wall diastolic thickness), elevated LV contractility (increases in LV ejection fraction, end-systolic pressure-volume relations, and preload recruitable stroke work), elevated LV and arterial stiffness (increased end-diastolic pressure-volume relationship and arterial elasticity), and LV oxidative stress (greater lipid peroxide content). Compared with female CIH offspring, male CIH offspring had more profound changes in blood pressure (BP), cardiac function, myocardial lipid peroxidase (LPO) content, and abdominal adiposity. Rodent prenatal CIH exposure, mimicking human maternal OSA, exerts detrimental morphological and cardiovascular effects on developing offspring; the model may provide useful insights of OSA effects in humans. NEW & NOTEWORTHY Obstructive sleep apnea is common in human pregnancy. Following maternal exposure to chronic intermittent hypoxia, a hallmark of sleep apnea, both sexes of rat offspring showed growth retardation, with males being more vulnerable to hypertension and dysfunctional left ventricular changes. This model is useful to study detrimental effects of maternal obstructive sleep apnea on developing offspring in humans.

Short-term intermittent hypoxia enhances sympathetic responses to continuous hypoxia in humans

2007 ◽  
Vol 103 (3) ◽  
pp. 835-842 ◽  
Author(s):  
Urs A. Leuenberger ◽  
Cynthia S. Hogeman ◽  
Sadeq Quraishi ◽  
Latoya Linton-Frazier ◽  
Kristen S. Gray
Keyword(s):  
Blood Pressure ◽  
Sleep Apnea ◽  
Sympathetic Activity ◽  
Intermittent Hypoxia ◽  
Muscle Sympathetic Nerve Activity ◽  
Acute Hypoxia ◽  
Short Term ◽  
Healthy Humans ◽  
Obstructive Sleep ◽  
Normal Humans

Short-term intermittent hypoxia leads to sustained sympathetic activation and a small increase in blood pressure in healthy humans. Because obstructive sleep apnea, a condition associated with intermittent hypoxia, is accompanied by elevated sympathetic activity and enhanced sympathetic chemoreflex responses to acute hypoxia, we sought to determine whether intermittent hypoxia also enhances chemoreflex activity in healthy humans. To this end, we measured the responses of muscle sympathetic nerve activity (MSNA, peroneal microneurography) to arterial chemoreflex stimulation and deactivation before and following exposure to a paradigm of repetitive hypoxic apnea (20 s/min for 30 min; O2 saturation nadir 81.4 ± 0.9%). Compared with baseline, repetitive hypoxic apnea increased MSNA from 113 ± 11 to 159 ± 21 units/min ( P = 0.001) and mean blood pressure from 92.1 ± 2.9 to 95.5 ± 2.9 mmHg ( P = 0.01; n = 19). Furthermore, compared with before, following intermittent hypoxia the MSNA (units/min) responses to acute hypoxia [fraction of inspired O2 (FiO2) 0.1, for 5 min] were enhanced (pre- vs. post-intermittent hypoxia: +16 ± 4 vs. +49 ± 10%; P = 0.02; n = 11), whereas the responses to hyperoxia (FiO2 0.5, for 5 min) were not changed significantly ( P = NS; n = 8). Thus 30 min of intermittent hypoxia is capable of increasing sympathetic activity and sensitizing the sympathetic reflex responses to hypoxia in normal humans. Enhanced sympathetic chemoreflex activity induced by intermittent hypoxia may contribute to altered neurocirculatory control and adverse cardiovascular consequences in sleep apnea.

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