Intermittent Hypoxia In Rats Research Articles

Cardiac Sympathetic Denervation Suppresses Atrial Fibrillation and Blood Pressure in a Chronic Intermittent Hypoxia Rat Model of Obstructive Sleep Apnea.

BackgroundChronic intermittent hypoxia (CIH) is a distinct pathological mechanism of obstructive sleep apnea (OSA), which is recognized as an independent risk factor for cardiovascular diseases. The aims of this study were to ascertain whether CIH induces atrial fibrillation (AF), to determine whether cardiac sympathetic denervation (CSD) can prevent it and suppress blood pressure, and to explore the potential molecular mechanisms involved.Methods and ResultsSixty Sprague‐Dawley male rats were randomly divided into 4 groups: sham, CSD, CIH, CIH+CSD. The rats were exposed either to CIH 8 hours daily or normoxia for 6 weeks. Cardiac pathology and structure were analyzed by hematoxylin and eosin staining and echocardiogram. ECG, blood pressure, body weight, and blood gas were recorded. Connexin 43 and tyrosine hydroxylase were detected by western blot, immunohistochemistry, and immunofluorescence. CIH induced atrial remodeling, and increased AF inducibility. CSD treatment reduced postapneic blood pressure rises and AF susceptibility, which could attenuate CIH‐associated structural atrial arrhythmogenic remodeling. In addition, CIH‐induced sympathetic nerve hyperinnervation and CSD treatment reduced sympathetic innervation, which may affect CIH‐induced AF‐associated sympathovagal imbalance. Connexin 43 was specifically downregulated in CIH, whereas CSD treatment increased its expression.ConclusionsThese results suggested CIH induces atrial remodeling, increases AF inducibility, results in sympathetic nerve hyperinnervation, and decreases connexin 43 expression, but CSD treatment reduces AF susceptibility, postapneic blood pressure increase, sympathetic innervation, and the alteration of Cx43, which may be a key point in the genesis of CIH‐induced AF.

Maternal chronic intermittent hypoxia in rats causes early atherosclerosis with increased expression of Caveolin-1 in offspring.

The objective of our research was to explore the effects of maternal and postpartum chronic intermittent hypoxia (CIH) exposure on atherosclerosis in adulthood offspring of rats, and the role of Caveolin-1 in the course. Sixteen rats were assigned to two groups (n = 8), maternal normoxia and CIH group. After delivery, two male pups per litter were selected and breastfed for 1month, which then randomly received postpartum normoxia or CIH. Thus, 4 groups were created as follows (n = 8): (1) maternal normoxia and postpartum normoxia group, (2) maternal CIH and postpartum normoxia group, (3) maternal CIH and postpartum CIH group, and (4) maternal normoxia and postpartum CIH group. The offspring were weighed at birth and weaning. After the duration of 12-week experiment, morphological changes, the expression of Caveolin-1 and NF-κB p65 in the aorta were detected. Maternal CIH resulted in significantly lower body weight and thicker intima (P < 0.001). CIH upregulated the expression of Caveolin-1 and NF-κB p65 significantly (P < 0.01). There was a synergistic effect of maternal and postpartum CIH on the thickening of intima (P < 0.05), also on the expression of Caveolin-1 and NF-κB p65 (P < 0.01). The results demonstrate that maternal CIH exposure causes a postpartum catch-up growth and early atherosclerotic changes followed by upregulating Caveolin-1 expression. Besides, maternal CIH enhances the atherosclerotic changes caused by postpartum CIH. Oxidative stress probably implicates in above effects.

Chronic Intermittent Hypoxia Alters Rat Ophthalmic Artery Reactivity Through Oxidative Stress, Endothelin and Endothelium-Derived Hyperpolarizing Pathways.

Obstructive sleep apnea recently has been associated with a higher frequency of ischemic optic neuropathies. Intermittent hypoxia (IH) has been proposed as a major component of obstructive sleep apnea cardiovascular consequences. However, there currently are no pathophysiologic data regarding the effect of IH on the ocular vascular system. Thus, we assessed the impact of chronic IH exposure on the morphology and vascular reactivity of the rat ophthalmic artery (OA). Rats were exposed to 14 days of IH or normoxia (NX). Ophthalmic artery reactivity was studied using wire myography in rats treated or not with tempol (1 mM/day). Expression of endothelin-1 (ET-1) and its receptors, and of the three nitric oxide synthase (NOS) isoform genes was quantified using quantitative polymerase chain reaction (qPCR) in the retina and optic nerve. Structural alterations (optical and electron microscopy) and superoxide anion production were studied in OA sections. Superoxide ion expression in the OA wall was increased by 23% after IH exposure. Ophthalmic artery contractile response to 3.10-8 M ET-1 was increased by 18.6% and nitric oxide-mediated relaxation was significantly delayed in IH compared to NX rats. In the absence of nitric oxide, cytochrome P450 blockade increased relaxation to acetylcholine in IH rats and delayed it in NX rats. Tempol treatment abolished the IH-induced changes in OA reactivity. These results strongly suggest that chronic IH induces oxidative stress in the rat OA, associated with endothelial dysfunction through alterations of nitric oxide and endothelium-derived hyperpolarising factors (EDHF) pathways.

Beneficial effects of tolvaptan on atrial remodeling induced by chronic intermittent hypoxia in rats.

Atrial remodeling in the form of fibrosis is considered as the substrate for the development of atrial fibrillation (AF). The aim of this study was to investigate the effects of tolvaptan on chronic intermittent hypoxia (CIH) induced atrial remodeling and the mechanisms underlying such changes. A total of 45 Sprague-Dawley rats were randomized into three groups: Control group, CIH group, CIH with tolvaptan treatment (CIH-T) group (n=15). CIH rats were subjected to CIH 6hour/d for 30days, and CIH-T rats were administrated tolvaptan while they received CIH. After the echocardiography examination, rats were sacrificed in the 31days. In each group, 5 rats were randomly selected for isolated heart electrophysiology testing, for other 10 rats, the tissues of atria were sampled for histological and molecular biological experiments, Masson's trichrome staining was used to evaluate the extent of atrial fibrosis, expression levels of microRNA-21 (miR-21), Sprouty-1 (Spry1), phosphatase, and tensin homolog (PTEN), extracellular regulated protein kinase (ERK), phospho-extracellular regulated protein kinase (p-ERK), matrix metalloprotein 9 (MMP-9), phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), phospho-protein kinase B (p-AKT), nuclear factor-k-gene binding (NF-κB), phosphor-nuclear factor-k-gene binding (p-NF-κB) were measured. Compared to the Control rats, CIH rats showed higher atrial interstitial collagen deposition and AF inducibility, mRNA levels of miR-21, MMP-9, PI3K, AKT, and protein levels of ERK, p-ERK, MMP-9, NF-κB, p-NF-κB were significantly increased, whereas mRNA levels of Spry1, ERK, and protein levels of Spry1, PTEN, PI3K, AKT, p-AKT were significantly decreased. Treatment with tolvaptan attenuated CIH-induced atrial fibrosis, reduced AF inducibility, expression levels of miR-21 and its downstream factors were also improved. CIH-induced significant atrial remodeling in our rat model, which was attenuated by tolvaptan. These changes may be explained due to alterations in miR-21/Spry1/ERK/MMP-9, miR-21/PTEN/PI3K/AKT, and NF-κB pathways by tolvaptan.

Hydrogen gas reduces chronic intermittent hypoxia-induced hypertension by inhibiting sympathetic nerve activity and increasing vasodilator responses via the antioxidation.

Molecular hydrogen is reported to be used medically to ameliorate various systemic pathological conditions. This study aimed to investigate the effect of hydrogen (H2 ) gas on hypertension induced by intermittent hypoxia in rats. The adult rats were exposed to chronic intermittent hypoxia (CIH) 8 hours/day for 5 weeks and/or H 2 gas 2 hours/day. We found that the systolic and diastolic blood pressure (BP) increased significantly in rats exposed to intermittent hypoxia, both of which were markedly attenuated after H treatment. Furthermore, intermittent hypoxia exposure elevated renal sympathetic nerve activity, consistent with plasma norepinephrine. Additionally, H 2 gas significantly improved CIH-induced abnormal vascular relaxation. Nevertheless, inhalation of H 2 gas alone did not cause such changes. Moreover, H 2 gas-treated rats exposed to CIH showed a significant reduction in 8-hydroxy-2 deoxyguanosine content and increases in superoxide dismutase activity, indicating improved oxidative stress. Taken together, these results indicate that H 2 gas has significant effects on the reduction of BP without any side effects. Mechanistically, inhibition of sympathetic activity and reduction of systemic vascular resistance may participate in this process via the antioxidant activity of H 2 .

MicroRNA-1249 regulates the apoptosis of myocardial cells in rats with chronic intermittent hypoxia by autophagy

Objective: To investigate the regulation and possible mechanism of microRNA (miR)-1249 on myocardial apoptosis in chronic intermittent hypoxia rats. Methods: A total of 16male SD rats aged 8 weeks were randomly divided into 2 groups by the random number table: normoxia control group and chronic intermittent hypoxia group (CIH) (n=8 each). The CIH group was exposed to intermittent hypoxia every day from 9: 00 to 17: 00 for 8 consecutive weeks, while the control group received the same frequency of pulse air. Hemodynamic values were measured via a cannula inserted into right common carotid artery. The expressions of miR-1249 and microtubule-associated protein light chain 3 (LC3) mRNA were observed by real-time PCR. The expressions of LC3 and Cleaved Caspase-3 were detected by Western bolt. TUNEL staining was performed to detect myocardial apoptosis. The rat cardiomyocyte cell H9C2 was divided into normoxia group, intermittent hypoxia (IH) group and miR-1249 inhibitor transfected and IH treatment group (inhibitor group). At the end of the experiment, the activation of LC3 protein in each group of cells was determined. Results: Compared with normoxia control group, left ventricle end diastolic pressure (LVEDP) increased [(4.6±0.4) vs (2.2±0.1) mmHg (1 mmHg=0.133 kPa)], left ventricular systolic pressure (LVSP) , maximal rate of pressure decline (-dp/dtmax), and maximal rate of pressure development (+ dp/dtmax) decreased in CIH group [(92.7±4.1) vs (135.3±3.2) mmHg, (4 247±108) vs (7 626±235) mmHg/s, and (3 168±105) vs (6 028±81) mmHg/s] (all P<0.001). The expression of miR-1249 and LC3 mRNA were significantly higher in CIH group than that in normoxia control group (all P<0.001), and a positive correlation was found between the expression of LC3 mRNA and miR-1249. The expression of LC3 and Cleaved Caspase-3 protein in myocardial tissue of CIH rats were significantly higher than that of the normoxia control group (all P<0.001). The proportion of myocardial cell apoptosis in CIH rats was significantly higher than that in the normoxia control group [(23.84±4.94)% vs (2.93±0.73)%] (P<0.001). The activation of LC3 in myocardial cells of inhibitor group was significantly lower than that of IH group, but higher than that in normoxia group. Conclusions: CIH could induce LC3 by raising the expression of miR-1249, and then induce the activation of apoptosis protein Caspase3. It ultimately induces myocardial apoptosis.

5-HT(2A) receptor/protein kinase C pathway in mediating long-term facilitation of carotid sinus nerve discharge in chronic intermittent hypoxia rats

Objective: To explore the role of 5-HT(2A)R/PKC pathway in mediating long-term facilitation (LTF) of carotid sinus nerve (CSN) discharge in chronic intermittent hypoxia (CIH) rats. Methods: With number table, 24 adult SD rats were randomly divided into saline control group (group A, n=6), 5-HT(2A)R antagonist (ketanserin) group (group B, n=6), PKC inhibitor (PKC θ-pseudosubstrate) group (group C, n=6) and combined ketanserin with PKC θ-pseudosubstrate group (group D, n=6). All rats were placed into the animal chambers for CIH treatment, 8 h per day (from 9: 00 to 17: 00) for 4 consecutive weeks. 28 days later, 5 min × 3 times of stimulation with acute intermittent hypoxia (AIH) were given, after that, stable CSN discharge activities were recorded and compared before and after intravenous injection of saline (group A), ketanserin (group B), PKC θ-pseudosubstrate (group C) or ketanserin + PKC θ-pseudosubstrate (group D), respectively. Results: There were no significant difference in the baseline (before AIH stimulation) average peak amplitude of CSN discharge among the four groups (P>0.05). In group A, the amplitude of CSN discharge at 30 min and 60 min after AIH were (5.01 ± 0.53) μV and (4.95 ± 0.34) μV respectively, which were significantly higher than that before AIH (P<0.01). The results implied that the CSN LTF could be induced by AIH in CIH pre-treatment rats. In group B, the amplitude of CSN discharge at 30 min and 60 min after AIH were (3.79 ± 0.42) μV and (3.73 ± 0.46) μV, respectively, which were still significantly higher than that before AIH (P<0.01), showing that carotid sinus nerve LTF couldn't be completely blocked by 5-HT(2A)R antagonist in rats. After injection of PKC θ-pseudosubstrate or ketanserin + PKC θ-pseudosubstrate in group C or D, there were no significant differences in CSN discharge amplitude before and after AIH (P>0.01), suggesting that inhibition of PKC alone or 5-HT(2A)R/PKC pathway could completely block the LTF of CSN. Conclusion: 5-HT(2A)R/PKC pathway was involved in mediating long-term facilitation of carotid sinus nerve discharge in CIH rats.

Pathogenesis of Abnormal Hepatic Lipid Metabolism Induced by Chronic Intermittent Hypoxia in Rats and the Therapeutic Effect of N-Acetylcysteine.

BackgroundThe pathogenesis of chronic intermittent hypoxia (CIH)-induced abnormal hepatic lipid metabolism in rats remains unclear. Here, we investigated the therapeutic effect of N-acetylcysteine (NAC) on abnormal hepatic lipid metabolism.Material/MethodsRats were subjected to hypoxia and NAC treatment, and evaluated in terms of hepatic lipid metabolism, hepatocyte ultrastructure, oxidative stress in hepatocytes, expression of nuclear factor-kappa B (NF-κB) and inflammatory cytokines (IL-1β, IL-6, and TNFα), serum lipoprotein lipase (LPL) levels, and blood lipids (triglycerides and cholesterol).ResultsCompared to the normoxic control group, animals in the hypoxic model group showed significant body weight gain; abnormal hepatic lipid metabolism; lipid vacuolization; accumulation of lipid droplets; abundant autophagosomes and lysosomes; significant increases in oxidative stress, inflammation level, and blood lipid levels; and significantly reduced LPL levels. Compared to control animals, rats in the treatment group exhibited normal body weight gain, improved lipid metabolism, fewer lipid droplets, alleviated ultrastructural injuries, decreased oxidative stress and inflammation level, as well as elevated LPL and reduced blood lipid levels.ConclusionsThe harmful effects of CIH on rat liver are possibly associated with the reactive oxygen species (ROS)/NF-κB signaling pathway. NAC is capable of attenuating lipid metabolism alterations and abnormal body weight gain in the CIH rat model, via a possible mechanism related to inhibition of ROS/NF-κB signaling.

Effects of losartan and allopurinol on cardiorespiratory regulation in obstructive sleep apnoea

What is the central question of this study? In sleep apnoea, a putative link between intermittent hypoxia and hypertension is the generation of oxygen radicals by angiotensinII and xanthine oxidase within the chemoreflex arc and vasculature. We tested whether chemoreflex control of sympathetic outflow, hypoxic vasodilatation and blood pressure are altered by angiotensin blockade (losartan) and/or xanthine oxidase inhibition (allopurinol). What is the main finding and its importance? Both drugs lowered blood pressure without altering sympathetic outflow, reducing chemoreflex sensitivity or enhancing hypoxic vasodilatation. Losartan and allopurinol are effective therapies for achieving blood pressure control in sleep apnoea. Chemoreflex sensitization produced by chronic intermittent hypoxia in rats is attenuated by angiotensinII type1 receptor (AT1 R) blockade. Both AT1 R blockade and xanthine oxidase inhibition ameliorate chronic intermittent hypoxia-induced endothelial dysfunction. We hypothesized that treatment with losartan and allopurinol would reduce chemoreflex sensitivity and improve hypoxic vasodilatation in patients with obstructive sleep apnoea. Eighty-six hypertensive patients with apnoea-hypopnoea index ≥25eventsh-1 and no other cardiovascular, pulmonary, renal or metabolic disease were randomly assigned to receive allopurinol, losartan or placebo for 6weeks. Treatment with other medications and/or continuous positive airway pressure remained unchanged. Tests of chemoreflex sensitivity and hypoxic vasodilatation were performed during wakefulness before and after treatment. Ventilation (pneumotachography), muscle sympathetic nerve activity (microneurography), heart rate (electrocardiography), arterial oxygen saturation (pulse oximetry), blood pressure (sphygmomanometry), forearm blood flow (venous occlusion plethysmography) and cerebral flow velocity (transcranial Doppler ultrasound) were measured during eupnoeic breathing and graded reductions in inspired O2 tension. Losartan and allopurinol lowered arterial pressure measured during eupnoeic breathing and exposure to acute hypoxia. Neither drug altered the slopes of ventilatory, sympathetic or cardiovascular responses to acute hypoxia. We conclude that losartan and allopurinol are viable pharmacotherapeutic adjuncts for achieving blood pressure control in hypertensive obstructive sleep apnoea patients, even those who are adequately treated with continuous positive airway pressure.

Sympathoexcitation following intermittent hypoxia in rat is mediated by circulating angiotensin II acting at the carotid body and subfornical organ

In anaesthetized rats, acute intermittent hypoxia increases sympathetic nerve activity, sympathetic peripheral chemoreflex sensitivity and central sympathetic-respiratory coupling. Renin-angiotensin system inhibition prevents the sympathetic effects of intermittent hypoxia, with intermittent injections of angiotensin II into the systemic circulation replicating these effects. Bilateral carotid body denervation reduces the sympathetic effects of acute intermittent hypoxia and eliminates the increases in chemoreflex sensitivity and sympathetic-respiratory coupling. Pharmacological inhibition of the subfornical organ also reduces the sympathetic effects of acute intermittent hypoxia, although it has no effect on the increases in chemoreflex sensitivity and central sympathetic-respiratory coupling. Combining both interventions eliminates the sympathetic effects of both intermittent hypoxia and angiotensin II. Circulating angiotensin II (AngII) is vital for arterial pressure elevation following intermittent hypoxia in rats, although its importance in the induction of sympathetic changes is unclear. We tested the contribution of the renin-angiotensin system to the effects of acute intermittent hypoxia (AIH) in anaesthetized and ventilated rats. There was a 33.7±2.9% increase in sympathetic nerve activity (SNA), while sympathetic chemoreflex sensitivity and central sympathetic-respiratory coupling increased by one-fold following AIH. The sympathetic effects of AIH were prevented by blocking angiotensin type 1 receptors with systemic losartan. Intermittent systemic injections of AngII (Int.AngII) elicited similar sympathetic responses to AIH. To identify the neural pathways responsible for the effects of AIH and Int.AngII, we performed bilateral carotid body denervation, which reduced the increase in SNA by 56% and 45%, respectively. Conversely, pharmacological inhibition of the subfornical organ (SFO), an established target of circulating AngII, reduced the increase in SNA following AIH and Int.AngII by 65% and 59%, respectively, although it did not prevent the sensitization of the sympathetic peripheral chemoreflex, nor the increase in central sympathetic-respiratory coupling. Combined carotid body denervation and inhibition of the SFO eliminated the enhancement of SNA following AIH and Int.AngII. Repeated systemic injections of phenylephrine caused an elevation in SNA similar to AIH, and this effect was prevented by a renin inhibitor, aliskiren. Our findings show that the sympathetic effects of AIH are the result of RAS-mediated activations of the carotid bodies and the SFO.

Mechanisms involved in the deleterious impact of intermittent hypoxia on ischemic cardiomyopathy

Chronic intermittent hypoxia (IH) is the hallmark feature of sleep-disordered breathing and clinical studies underlie a poor prognosis in severe apneic patients post-myocardial infarction (MI). Thus, it is necessary to understand specific mechanistic pathways involved in this post-MI aggravation, in order to improve the management of patient. Previous studies showed that IH activates myocardial HIF1-endoplasmic reticulum (ER) stress axis. Thus, we aimed at highlighting: 1 the impact of IH on the development of ischemic cardiomyopathy; 2 to determine the involved mechanisms, in particular the role of IH on HIF1-ER stress axis, sympathetic activation and calcium (Ca 2+ ) homeostasis perturbations. MI was induced by permanent ligation of the left coronary artery in male Wistar rats. Then, rats were exposed to IH (21–5% FiO 2 , 60 s cycle, 8 h/day) or normoxia (N) for 1 to 12 weeks. Cardiac function was evaluated by ultrasonography and cardiac catheterization. Ultimately, hearts were withdrawn for biochemical and histological analysis, as well as Ca 2+ transient imaging after cardiomyocytes isolation. We observed more important alterations in ejection fraction, dP/dtmax, and dP/dtmin in IH rats compared to N. These IH rats exhibited sympathetic hyperactivation (i.e. increased LF/HF ratio and adrenal gland hypertrophy), which was associated with an increased HIF1 expression post-MI. Expressions of GRP78, CHOP and caspase 12 proteins were also increased by IH, suggesting a pro apoptotic ER stress. Except from phospholamban that was hyper-phosphorylated, Ca 2+ handling protein expressions were not different between N and IH. Finally, Ca 2+ transient analysis is ongoing. As in severe apneic patients, we showed that IH is deleterious on ischemic cardiomyopathy development. Besides, HIF1, sympathetic activity, ER stress and Ca 2+ homeostasis are disturbed. Further studies are needed to better understand the relationship between these mechanisms.

Role of the endogenous cannabinoid receptor 1 in brain injury induced by chronic intermittent hypoxia in rats

ABSTRACTPurpose: This study investigated the effect of rimonabant, a cannabinoid receptor type 1 antagonist, on calcium/calmodulin- dependent protein kinase II and cannabinoid receptor type 1 in chronic intermittent hypoxia.Materials and methods: Healthy male rats were divided into control group, intermittent hypoxia group for 4 or 6 weeks, hypoxic intervention group that received rimonabant (1 mg/kg/d) before exposure to hypoxia for 4 or 6 weeks (n = 10/group). Morphological changes and expressions of the two indexes in the cerebral hippocampus cells were determined by haematoxylin–eosin staining and immunohistochemistry, respectively.Results: In the intermittent hypoxia group at 4 weeks, the hippocampal cells were damaged with sparse cytoplasm and unclear boundaries, which are even worse at 6 weeks. In contrast, the hippocampal cells of the hypoxic intervention group were neatly arranged at 4 weeks. At 6 weeks, cells were larger with scarce cytoplasm and nuclear changes indicative of cell death. Calcium/calmodulin-dependent protein kinase II and cannabinoid receptor type 1 expression in the cerebral hippocampus was elevated in the intermittent hypoxia group at 4 weeks with even greater at 6 weeks. Cannabinoid receptor type 1 expression was reduced in the hypoxic intervention group compared to the intermittent hypoxia group. Correlation analysis revealed significant positive correlation of them in the intermittent hypoxia group.Conclusions: Chronic intermittent hypoxia induced structural damage in the hippocampus and increased cannabinoid receptor type 1 and calcium/calmodulin-dependent protein kinase II expression, which may mediate cognitive impairment associated with chronic intermittent hypoxia. Rimonabant had a protective effect against chronic intermittent hypoxia.

Improvement of hydrogen on liver oxidative stress injury in chronic intermittent hypoxia rats

To explore the effects of hydrogen on liver injury in chronic intermittent hypoxia rats and the related oxidative stress mechanism. Twenty-four male adult SD rats were randomly divided into 3 groups(n=8):the normoxia group (Norm), the chronic intermittent hypoxia group (CIH), the chronic intermittent hypoxia and hydrogen group (H2 + CIH). Rats in Norm group were exposed in air, those in the other 2 groups suffered from chronic intermittent hypoxia conditions for 5 weeks. Before the CIH treatment, rats in H2+CIH group inhaled hydrogen gas at 67% concentration for 1 hour. The serum biochemical indicators of oxidative stress, pro-inflammatory cytokine, liver enzyme and blood lipid were inspected after five weeks treatment, the pathological changes of liver tissue were also observed in the transmission electron microscope. Compared with Norm group, the microstructure of liver cells was severely injured, and the serum levels of glutamic-pyruvic transaminase(ALT),glutamic-oxalacetic transaminase (AST) were significantly higher in CIH group (P<0.05); the serum level of 8-hydroxy-2 deoxyguanosine(8-OHdG) and interleukin-6(IL-6) was significantly higher, the serum level of superoxide dismutase (SOD) was significantly lower. Compared with CIH group, the pathology of liver microstructure were significantly improved and the serum levels of ALT, AST were significantly lower in H2+CIH group (P<0.05); the serum levels of 8-OHdG and IL-6 were significantly lower, the serum level of SOD was significantly higher. Compared with Norm group, the serum level of IL-1 was higher, the serum level of TC, TG, and low density lipoprotein(LDL) were lower, but there was no statistical difference with those in CIH group. There was no statistical difference in the serum level of high density lipoprotein (HDL)among the three groups. Pre-treatment with hydrogen could improve the liver injury caused by chronic intermittent hypoxia, and reducing oxidative stress level for protecting the liver cells damage.

Impact about the endogenous cannabinoid receptor 1 on brain injury of chronic intermittent hypoxia in rat

Impact about the endogenous cannabinoid receptor 1 on brain injury of chronic intermittent hypoxia in rat

Early gestational intermittent hypoxia in rats induces delayed changes in immune and redox homeostasis with lasting perivascular placental edema

Early gestational intermittent hypoxia in rats induces delayed changes in immune and redox homeostasis with lasting perivascular placental edema

Intermittent Hypoxia Improves Atherosclerosis Associated with Upregulation of Hif-1α and Nf-κB in Aortic Arch and Serum of Rabbits

Objectives To investigate the role of HIF-1α and NF-κB in intermittent hypoxia (IH) induced atherosclerosis in rabbits. Methods New-Zealand White rabbits were exposed to IH for 12 weeks (intermittent hypoxia of 21% O2 for 30 s and 8% O2 for 30 s, cyclically repeated for 8 h/day). We randomly assigned 48 male rabbits to groups of normoxia (RA) or IH. The rabbits in the RA group were continuously exposed to room air. After intervention of 4, 8, and 12 weeks, serum and aortic arch tissues were subjected to Elisa and immunohistochemical staining analyses respectively. The formation of atherosclerosis in the aortic arch was observed by HE. Results The formation of atherosclerosis in aortic tissue was observed by HE staining after IH. Compared with the RA rats, the level of HIF-1α and NF-κB in the serum of IH rats started to increase 4, 8, and 12 weeks after the beginning of the experiment (p 0.05). NF-κB protein expression was significantly increased after IH (p Conclusions IH may, through increased HIF-1α and NF-κB in rabbits, lead to lipid deposition, which leads to the formation of atherosclerosis and the occurrence of cardiovascular and cerebrovascular diseases.

Effects of Exercise-Induced Irisin on Cardiac Fibrosis Resulted from the Combination of Obesity and Intermittent Hypoxia in Rats

Effects of Exercise-Induced Irisin on Cardiac Fibrosis Resulted from the Combination of Obesity and Intermittent Hypoxia in Rats

Stimulatory Effect of Intermittent Hypoxia on the Production of Corticosterone by Zona Fasciculata-Reticularis Cells in Rats

Hypoxia or intermittent hypoxia (IH) have known to alter both synthesis and secretion of hormones. However, the effect of IH on the production of adrenal cortical steroid hormones is still unclear. The aim of present study was to explore the mechanism involved in the effect of IH on the production of corticosterone by rat ZFR cells. Male rats were exposed at 12% O2 and 88% N2 (8 hours per day) for 1, 2, or 4 days. The ZFR cells were incubated at 37 °C for 1 hour with or without ACTH, 8-Br-cAMP, calcium ion channel blockers, or steroidogenic precursors. The concentration of plasma corticosterone was increased time-dependently by administration of IH hypoxia. The basal levels of corticosterone production in cells were higher in the IH groups than in normoxic group. IH resulted in a time-dependent increase of corticosterone production in response to ACTH, 8-Br-cAMP, progesterone and deoxycorticosterone. The production of pregnenolone in response to 25-OH-C and that of progesterone in response to pregnenolone in ZFR cells were enhanced by 4-day IH. These results suggest that IH in rats increases the secretion of corticosterone via a mechanism at least in part associated with the activation of cAMP pathway and steroidogenic enzymes.

Inhibition of Rho-kinase Attenuates Left Ventricular Remodeling Caused by Chronic Intermittent Hypoxia in Rats via Suppressing Myocardial Inflammation and Apoptosis.

Chronic intermittent hypoxia (CIH), the hallmark of obstructive sleep apnea syndrome (OSAS), has been reported to play a key role in the development of OSAS-associated cardiovascular diseases including cardiac remodeling. RhoA/Rho-kinase (ROCK) pathway has also been implicated in myocardial remodeling, but the exact mechanisms are not fully elucidated. This study's purpose is to investigate the influence of fasudil, a selective ROCK inhibitor, on CIH-induced left ventricular remodeling in rats and its possible mechanisms. Adult male Sprague-Dawley rats suffered from CIH or normoxia stimulus and were intervened with vehicle or fasudil (10 mg·kg·d, intraperitoneal injection) for 6 weeks. In this study, treatment with fasudil significantly reversed intermittent hypoxia-induced histopathological transformations and ultrastructural changes in rat myocardium. Moreover, fasudil downregulated the protein levels of RhoA and phosphorylation of myosin phosphatase targeting subunit-1 (MYPT1), thus effectively inhibited the activation of RhoA/ROCK signaling pathway. Simultaneously, activity of nuclear factor (NF)-kB was suppressed by fasudil, which was accompanied by reduced NF-kB downstream inflammatory genes including interleukin-6, tumor necrosis factor-a and monocyte chemotactic protein-1, and apoptosis. These results suggest that fasudil attenuates myocardial remodeling in CIH rats, at least partly by suppressing activation of NF-kB. Inhibition of the RhoA/ROCK pathway could become an important therapeutic target in the prevention of OSAS-related cardiomyopathy.

The effects of chronic intermittent hypoxia on blood pressure and myocardial mitochondrial oxidative stress in aged rats

Objective To investigate the effect of chronic intermittent hypoxia on blood pressure, sympathetic nerve activity and myocardial mitochondrial oxidative stress status in aged rats. Methods Chronic intermittent hypoxia(CIH)rat models were established.A total of 84 male Wistar rats(3-4 and 23-24 months old, respectively)were randomly and equally divided into four groups according to age: young control group, young CIH group, aged control group and aged CIH group.CIH exposure lasted for 3 weeks.The arterial blood pressure, the frequency of carotid sinus nerve action potential, the lung function, the levels of catecholamine, aconitase/fumarate ratio(A/F), plasma superoxide dismutase(SOD)in the plasma were measured and compared between four groups. Results The arterial blood pressure was significantly higher in young CIH group than in the young control group〔(150.4±25.6)mmHg vs.(102.2±7.4)mmHg, P<0.01〕. There was no significant difference in the arterial blood pressure between the aged CIH group〔(132.8±16.2)mmHg〕and the aged control group〔(127.1±26.8)mmHg〕. The minute volume ventilation was significantly lower in the aged control group than in young control group〔(331.7±53.5)ml·min-1·kg-1vs.(554.8±111.9)ml·min-1·kg-1P<0.05〕. The min-1·kg-1 ventilation showed no significant difference between the aged CIH group〔(354.1±51.9)ml·min-1·kg-1〕and the aged control group〔(331.7±53.5)ml·min-1·kg-1〕. The rate of CSN frequency change by hypoxia stimulation was lower in the aged control group than in young control group〔(6.2±5.5)times vs.(11.8±6.6)times, P<0.01〕, and was lower in the aged CIH group than in the young CIH group〔(22.2±13.5)times vs.(44.2±12.1)times, P<0.01〕. The levels of plasma norepinephrine and epinephrine were higher in the young CIH group than in the control group〔(39.0±8.9)nmol/L vs.(20.8±10.6)nmol/L, (48.1±13.6)nmol/L vs.(26.7±14.3)nmol/L, both P<0.05〕. The levels of plasma norepinephrine and epinephrine showed no significant difference between the aged control group and the young control group, also no significant difference was found between the aged CIH group and the aged control group.The A/F ratio was lower in the young CIH group than in the young control group〔(0.26±0.13)vs.(0.58±0.04), P<0.01〕. The A/F ratio was lower in the aged control group than in the young control group〔(0.29±0.02)vs.(0.58±0.04), P<0.01〕, but there was no significant difference in the A/F ratio between the aged CIH group and the aged control group.The level of SOD was significantly lower in the young CIH group than in the young control group〔(5.30±0.90)NU/mgprot vs.(6.10±1.73)NU/mgprot, P<0.05〕. There was no significant difference in SOD level between aged control group and aged CIH group. Conclusions The effect of CIH on blood pressure in aged rats is different from the youth rats.This study shows adecreasedsympathetic nervous over-activity and a reducedmitochondrial oxidative stress in aged rats.Aging probably suppresses two important pathogenic mechanisms, by which CIH affects blood pressure, therefore releases CIH-induced blood pressure abnormality. Key words: Pulmonary disease, chronic obstructive; Cell hypoxia; Hypertension; Cell aging