Dynamic time-varying analysis of heart rate and blood pressure variability in cats exposed to short-term chronic intermittent hypoxia

2008 ◽  
Vol 295 (1) ◽  
pp. R28-R37 ◽  
Author(s):  
Sergio Rey ◽  
Mika P. Tarvainen ◽  
Pasi A. Karjalainen ◽  
Rodrigo Iturriaga
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Intermittent Hypoxia ◽  
Acute Hypoxia ◽  
Low Frequency ◽  
Dynamic Responses ◽  
Chronic Intermittent Hypoxia ◽  
Short Term ◽  
Obstructive Sleep ◽  
Induced Hypertension

Chronic intermittent hypoxia (CIH) contributes to the development of hypertension in patients with obstructive sleep apnea and animal models. However, the early cardiovascular changes that precede CIH-induced hypertension are not completely understood. Nevertheless, it has been proposed that one of the possible contributing mechanisms to CIH-induced hypertension is a potentiation of carotid body (CB) hypoxic chemoreflexes. Therefore, we studied the dynamic responses of heart rate, blood pressure, and their variabilities during acute exposure to different levels of hypoxia after CIH short-term preconditioning (4 days) in cats. In addition, we measured baroreflex sensitivity (BRS) on the control of heart rate by noninvasive techniques. To assess the relationships among these indexes and CB chemoreflexes, we also recorded CB chemosensory discharges. Our data show that short-term CIH reduced BRS, potentiated the increase in heart rate induced by acute hypoxia, and was associated with a dynamic shift of heart rate variability (HRV) spectral indexes toward the low-frequency band. In addition, we found a striking linear correlation ( r = 0.97) between the low-to-high frequency ratio of HRV and baseline. CB chemosensory discharges in the CIH-treated cats. Thus, our results suggest that cyclic hypoxic stimulation of the CB by short-term CIH induces subtle but clear selective alterations of HRV and BRS in normotensive cats.

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.

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.

Invited Review: Physiological consequences of intermittent hypoxia: systemic blood pressure

2001 ◽  
Vol 90 (4) ◽  
pp. 1600-1605 ◽  
Author(s):  
Eugene C. Fletcher
Keyword(s):  
Blood Pressure ◽  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Intermittent Hypoxia ◽  
Cardiovascular Response ◽  
Acute Hypoxia ◽  
Renin Angiotensin System ◽  
Systemic Blood Pressure ◽  
Angiotensin Ii Receptor ◽  
Obstructive Sleep

One of the major manifestations of obstructive sleep apnea is profound and repeated hypoxia during sleep. Acute hypoxia leads to stimulation of the peripheral chemoreceptors, which in turn increases sympathetic outflow, acutely increasing blood pressure. The chronic effect of these repeated episodic or intermittent periods of hypoxia in humans is difficult to study because chronic cardiovascular changes may take many years to manifest. Rodents have been a tremendous source of information in short- and long-term studies of hypertension and other cardiovascular diseases. Recurrent short cycles of normoxia-hypoxia, when administered to rats for 35 days, allows examination of the chronic cardiovascular response to intermittent hypoxia patterned after the episodic desaturation seen in humans with sleep apnea. The result of this type of intermittent hypoxia in rats is a 10- to 14-mmHg increase in resting (unstimulated) mean blood pressure that lasts for several weeks after cessation of the daily cyclic hypoxia. Carotid body denervation, sympathetic nerve ablation, renal sympathectomy, adrenal medullectomy, and angiotensin II receptor blockade block the blood pressure increase. It appears that adrenergic and renin-angiotensin system overactivity contributes to the early chronic elevated blood pressure in rat intermittent hypoxia and perhaps to human hypertension associated with obstructive sleep apnea.

scholarly journals The Na+/Ca2+ exchanger-1 mediates left ventricular dysfunction in mice with chronic intermittent hypoxia

2010 ◽  
Vol 109 (6) ◽  
pp. 1675-1685 ◽  
Author(s):  
Ling Chen ◽  
Jin Zhang ◽  
Xuejiao Hu ◽  
Kenneth D. Philipson ◽  
Steven M. Scharf
Keyword(s):  
Blood Pressure ◽  
Intermittent Hypoxia ◽  
Diastolic Pressure ◽  
Left Ventricular ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Heart Weight ◽  
Chronic Intermittent Hypoxia ◽  
Lv Dysfunction ◽  
Obstructive Sleep ◽  
Lower Ejection Fraction

Chronic intermittent hypoxia (CIH) and cardiovascular dysfunction occur in patients with obstructive sleep apnea. We hypothesized that the Na+/Ca2+ exchanger-1 (NCX1) mediates, at least partially, left ventricular (LV) dysfunction in CIH. Four groups of mice ( N = 15–17 per group), either cardiac-specific NCX1 knockouts (KO) or wild types (WT), were exposed to either CIH or normoxia [i.e., handled controls (HC)] 10 h/day for 8 wk. As expected, myocardial expression of NCX1 was greater in WT than in KO animals, both in HC and CIH-exposed groups. In both CIH groups (WT or KO), but not the HC groups, blood pressure increased by 10% at week 1 over their baseline and remained elevated for all 8 wk, with no differences between WT and KO. LV dilation (increased diastolic and systolic dimension) and hypertrophy (increased left heart weight), along with LV dysfunction (greater end-diastolic pressure and lower ejection fraction), were observed in the WT animals compared with the KO following CIH exposure. Compared with HC, CIH exposure was associated with apoptosis (terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling and caspase-3) in WT, but not KO, mice. We conclude that myocardial NCX1 does not mediate changes in blood pressure, but is one of the mediators for LV global dysfunction and cardiomyocyte injury in CIH.

scholarly journals Intermittent Hypoxia-Induced Carotid Body Chemosensory Potentiation and Hypertension Are Critically Dependent on Peroxynitrite Formation

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Esteban A. Moya ◽  
Paulina Arias ◽  
Carlos Varela ◽  
María P. Oyarce ◽  
Rodrigo Del Rio ◽  
...  
Keyword(s):  
Carotid Body ◽  
Reactive Nitrogen Species ◽  
Intermittent Hypoxia ◽  
Acute Hypoxia ◽  
Systemic Hypertension ◽  
Chronic Intermittent Hypoxia ◽  
Sprague Dawley ◽  
Arterial Blood ◽  
Sprague Dawley Rats ◽  
Obstructive Sleep

Oxidative stress is involved in the development of carotid body (CB) chemosensory potentiation and systemic hypertension induced by chronic intermittent hypoxia (CIH), the main feature of obstructive sleep apnea. We tested whether peroxynitrite (ONOO−), a highly reactive nitrogen species, is involved in the enhanced CB oxygen chemosensitivity and the hypertension during CIH. Accordingly, we studied effects of Ebselen, an ONOO−scavenger, on 3-nitrotyrosine immunoreactivity (3-NT-ir) in the CB, the CB chemosensory discharge, and arterial blood pressure (BP) in rats exposed to CIH. Male Sprague-Dawley rats were exposed to CIH (5% O2, 12 times/h, 8 h/day) for 7 days. Ebselen (10 mg/kg/day) was administrated using osmotic minipumps and BP measured with radiotelemetry. Compared to the sham animals, CIH-treated rats showed increased 3-NT-ir within the CB, enhanced CB chemosensory responses to hypoxia, increased BP response to acute hypoxia, and hypertension. Rats treated with Ebselen and exposed to CIH displayed a significant reduction in 3-NT-ir levels (60.8 ± 14.9 versus 22.9 ± 4.2 a.u.), reduced CB chemosensory response to 5% O2(266.5 ± 13.4 versus 168.6 ± 16.8 Hz), and decreased mean BP (116.9 ± 13.2 versus 82.1 ± 5.1 mmHg). Our results suggest that CIH-induced CB chemosensory potentiation and hypertension are critically dependent on ONOO−formation.

scholarly journals Hematological Changes in Chronic Sustained Hypoxia and Chronic Intermittent Hypoxia in a Mouse Model

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3525-3525
Author(s):  
Jihyun Song ◽  
Krishna M Sundar ◽  
John Hoidal ◽  
Josef T. Prchal
Keyword(s):  
Mouse Model ◽  
Intermittent Hypoxia ◽  
Conflicts Of Interest ◽  
Acute Hypoxia ◽  
Chronic Intermittent Hypoxia ◽  
Endocrine Regulation ◽  
Mitochondrial Mass ◽  
Mitochondrial Ros ◽  
Obstructive Sleep ◽  
Sustained Hypoxia

Hypoxia alters cellular metabolism and chemosensory endocrine regulation. Hypoxia increases production of erythrocytes in order to improve oxygen delivery to tissues. Organisms respond differentially to duration and patterns of hypoxia. Acute hypoxia stabilizes transcription factors' a-subunits of hypoxia inducible factors (HIFs; HIF-1a and HIF-2a) while in chronic hypoxia HIF-2a continues to be augmented, but HIF-1a decreases (1, 2). There are two clinical patterns of hypoxia: chronic sustained hypoxia (CSH) and chronic intermittent hypoxia (CIH). CSH is present in people living at high altitudes, patients with respiratory diseases, and Eisenmenger complex. CIH is characterized by repeated series of hypoxia followed by normoxia exposure and best exemplified by obstructive sleep apnea (OSA). The hematological responses to CSH and CIH has not been compared and studied in detail. We studied 2 separate hypoxic mouse cohorts: 1) CSH (12% O2 for 24 hours/day for 33 days), and 2) CIH emulating human OSA (8% O2 for 30 sec followed by 21% O2 for 90 sec; 8 hours/day for 33 days) and nonhypoxic controls. Hematocrits (Hct) were higher in both CSH and CIH compared to controls. In CSH, Hct increased by 22.0% (p <0.0001) and by 7.6% in CIH (p=0.0115). To evaluate the effect of CSH and CIH on erythron we measured erythropoietin (Epo) and reticulocytes. Reticulocytes were lower in CSH and CIH compared to controls; however, CIH tended to have higher reticulocytes than CSH (p=0.0607). Epo levels decreased in CSH and CIH but not significantly in contrast to increased Epo detected at 3 days after acute hypoxia (2). These Epo levels were reflected by decrease of Epo transcripts in kidney after 33 days of CSH (p=0.0001). In contrast, there was no decrease of Epo kidney transcripts in CIH. Hepcidin (encoded by Hamp) is the principal regulator of iron metabolism; its expression is decreased by hypoxia, iron deficiency, and augmented erythropoiesis. It suppresses erythropoiesis by inhibiting release iron from macrophages. We measured Hamp transcript in the liver. Despite presence of hypoxia, both CSH and CIH had higher Hamp transcripts. These results are consistent with co-existent suppression of erythropoiesis in both CSH and CIH, but more so in CSH. Since inflammation induces hepcidin expression, we measured inflammatory marker transcripts in granulocytes and found increased Il-6 transcripts in both CSH and CIH; Il-1a levels increased only in CSH. As Epo transcripts were decreased in the kidney, we also measured inflammatory markers` transcripts in kidney. The Ccl2, Il-10 and Il-6 transcripts were higher in both CSH and CIH. These results suggest that increased inflammation in CSH and CIH suppresses erythropoiesis via increase of hepcidin. We also measured reactive oxygen species (ROS) in blood cells. The amount of mitochondrial ROS and the number of mitochondrial ROS positive reticulocytes increased in CSH and CIH and correlated with mitochondrial mass. We previously showed that excessive ROS associated with increased mitochondrial mass is due to reduced Bnip3L (the mediator of mitophagy) and decreased catalase upon normoxic return from CSH (2). Bnip3L and Cat (encodes catalase) were also decreased in both CSH and CIH in reticulocytes, which correlated with their increased mitochondrial mass and ROS. We conclude that in CIH there is an increased hematocrit in mouse OSA model which contrasts with human OSA where Hct is not increased. Our data support that the increased Hct occurs in CSH and mouse CIH at the early stages of hypoxia, but that further increases of Hct is prevented by inflammation and hepcidin. The high Hct is further contributed by recent demonstration of prolonged mouse erythrocyte survival in hypoxia (4). Further, in this OSA mouse model increased ROS is restricted to reticulocytes but not present in leukocytes, unlike in human OSA (3). This demonstrates some limitation of using mouse as a model for human OSA, but also some similarities. Excessive ROS in reticulocytes due to increased mitochondrial mass and decreased catalase (due to a decrease of HIF-1a) may explain some features of pathophysiology of CSH and CIH (2). 1. Uchida et al, JBC 2004 2. Song et al, JMM 2015 3. Song et al," Normal Hemoglobin Concentrations in OSA", abstract this meeting 4. Song et al, High Alt Med Biol. 2019 Disclosures No relevant conflicts of interest to declare.

scholarly journals Effects of allergic airway inflammation and chronic intermittent hypoxia on systemic blood pressure

2020 ◽  
Vol 319 (5) ◽  
pp. R566-R574
Author(s):  
Ashish Chaddha ◽  
Oleg Broytman ◽  
Mihaela Teodorescu
Keyword(s):  
Blood Pressure ◽  
Pulmonary Function ◽  
Airway Inflammation ◽  
Intermittent Hypoxia ◽  
Systemic Blood Pressure ◽  
Brown Norway ◽  
Systemic Hypertension ◽  
Chronic Intermittent Hypoxia ◽  
Systemic Blood ◽  
Obstructive Sleep

Asthma and obstructive sleep apnea (OSA) are highly prevalent chronic conditions, and both are associated with systemic hypertension. Additionally, asthma and OSA reciprocally interact, mutually exacerbating each other. In this study, we tested the effect of allergen-induced lower airway inflammation and concurrent chronic intermittent hypoxia (CIH) on systemic blood pressure (BP), pulmonary function, and proinflammatory cytokines, in a rat model. Brown Norway rats were exposed to 43 days of normoxia (NORM) or CIH, concurrent with weekly house dust mite (HDM) challenges. BP was measured 1 day after the last HDM challenge. On day 44, pulmonary function was tested, and blood for Th-2 and Th-1 cytokine levels was collected. HDM significantly increased mean ( P = 0.002), systolic ( P = 0.003), and diastolic ( P = 0.004) BP compared with saline-challenged controls. Higher mean BP significantly correlated to increased total respiratory system resistance ( R2 = 0.266, P = 0.002), driven by an association with parenchymal tissue dampening ( R2 = 0.166, P = 0.016). HDM relative to saline-challenged controls increased the expression of serum IL-6 ( P = 0.008), but no relationships of systemic BP with IL-6 or any other cytokines were found. CIH did not alter the allergen-induced responses on BP, although it tended to increase the expression of serum IL-6 ( P = 0.06) and monocyte chemoattractant protein-1 (MCP-1, P = 0.09), regardless of HDM challenge. Chronic allergen-induced airway inflammation results in systemic hypertension that is correlated to the degree of distal airway obstruction induced by the allergen. These effects do not appear to be explained by the associated systemic inflammation.

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.

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