• The Korean Journal of Physiology and Pharmacology
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• v.3 no.4
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• pp.393-404
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• 1999

We have reported that hypoxia stimulates EDRF(s) release from endothelial cells and the release may be augmented by previous hypoxia. As a mechanism, it was hypothesized that reoxygenation can stimulate EDRF(s) release from endothelial cells and we tested the hypothesis via bioassay experiment. In the bioassay experiment, rabbit aorta with endothelium was used as EDRF donor vessel and rabbit carotid artery without endothelium as a bioassay test ring. The test ring was contracted by prostaglandin $F_{2a}\;(3{\times}10^{-6}\;M)$ which was added to the solution perfusing through the aorta. Hypoxia was evoked by switching the solution aerated with 95% $O_2/5%\;CO_2$ mixed gas to one aerated with 95% $O_2/5%\;CO_2$ mixed gas. Hypoxia/reoxygenation were interexchanged at intervals of 2 minutes (intermittent hypoxia). In some experiments, endothelial cells were exposed to 10-minute hypoxia (continuous hypoxia) and then exposed to reoxygenation and intermittent hypoxia. In other experiments, the duration of reoxygenation was extended from 2 minutes to 5 minutes. When the donor aorta was exposed to intermittent hypoxia, hypoxia stimulated EDRF(s) release from endothelial cells and the hypoxia-induced EDRF(s) release was augmented by previous hypoxia/reoxygenation. When the donor aorta was exposed to continuous hypoxia, there was no increase of hypoxia-induced EDRF(s) release during hypoxia. But, after the donor aorta was exposed to reoxygenation, hypoxia-induced EDRF(s) release was markedly increased. When the donor aorta was pretreated with nitro-L-arginine $(10^{-5}$ M for 30 minutes), the initial hypoxia-induced EDRF(s) release was almost completely abolished, but the mechanism for EDRF(s) release by the reoxygenation and subsequent hypoxia still remained to be clarified. TEA also blocked incompletely hypoxia-induced and hypoxia/reoxygenation-induced EDRF(s) release. EDRF(s) release by repetitive hypoxia and reoxygenation was completely blocked by the combined treatment with nitro-L-arginine and TEA. Cytochrome P450 blocker, SKF-525A, inhibited the EDRF(s) release reversibly and endothelin antgonists, BQ 123 and BQ 788, had no effect on the release of endothelium-derived vasoactive factors. Superoxide dismutase (SOD) and catalase inhibited the EDRF(s) release from endothelial cells. From these data, it could be concluded that reoxygenation stimulates EDRF(s) release and hypoxia/reoxygenation can release not only NO but also another EDRF from endothelial cells by the production of oxygen free radicals.

• The Korean Journal of Physiology and Pharmacology
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• v.2 no.2
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• pp.209-216
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• 1998

The present study was designed: (1) to determine whether or not hypoxia stimulates the release of endothelium-derived relaxing factors (EDRFs) from endothelial cells, and (2) to examine whether or not the hypoxia-induced EDRFs release is further augmented by previous hypoxia-reoxygenation, using bioassay system. In the bioassay experiment, rabbit aorta with endothelium was used as EDRFs donor vessel and rabbit carotid artery without endothelium as a bioassay test ring. The test ring was contracted by prostaglandin $F_{2{\alpha}}$ $(3{\times}10^{-6}\;M/L)$, which was added to the solution perfusing through the aortic segment. Hypoxia was evoked by switching the solution aerated with 95% $O_2/5%\;CO_2$ mixed gas to one aerated with 95% $N_2/5%\;CO_2$ mixed gas. When the contraction induced by prostaglandin $F_{2{\alpha}}$ reached a steady state, the solution was exchanged for hypoxic one. And then, hypoxia and reoxygenation were interchanged at intervals of 2 minutes (intermittent hypoxia). The endothelial cells were also exposed to single 10-minute hypoxia (continuous hypoxia). When the bioassay ring was superfused with the perfusate through intact aorta, hypoxia relaxed the precontracted bioassay test ring markedly. Whereas, when bioassay ring was superfused with the perfusate through denuded aorta or polyethylene tubing, hypoxia relaxed the precontracted ring slightly. The relaxation was not inhibited by indomethacin but by nitro-L-arginine or methylene blue. The hypoxia-induced relaxation was further augmented by previous hypoxia-reoxygenation and the magnitude of the relaxation by intermittent hypoxia was significantly greater than that of the relaxation by continuous hypoxia. The results suggest that hypoxia stimulates EDNO release from endothelial cells and that the hypoxia-induced EDNO release is further augmented by previous hypoxia-reoxygenation.

• Yonsei Medical Journal
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• v.59 no.9
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• pp.1079-1087
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• 2018

Purpose: Obstructive sleep apnea and chronic obstructive pulmonary disease are independent risk factors of cardiovascular disease (CVD), and their coexistence is known as overlap syndrome (OS). Endothelial dysfunction is the initial stage of CVD; however, underlying mechanisms linking OS and CVD are not well understood. The aim of this study was to explore whether OS can lead to more severe inflammation and endothelial apoptosis by promoting endothelial dysfunction, and to assess the intervention effects of antioxidant tempol. Materials and Methods: Male Wistar rats (n=66) were exposed to normal oxygen [normal control (NC) group], intermittent hypoxia (IH group), cigarette smoke (CH group), as well as cigarette smoke and IH (OS group). Tempol intervention was assessed in OS group treated with tempol (OST group) or NaCl (OSN group). After an 8-week challenge, lung tissues, serum, and fresh blood were harvested for analysis of endothelial markers and apoptosis. Results: The levels of intracellular adhesion molecule-1, vascular cellular adhesion molecule-1, and apoptosis in circulating epithelial cells were the highest in OS group and the lowest in NC group. These levels were all greater in IH group than in CH group, and were lower in OST group than in OS and OSN groups (all p<0.001). Conclusion: Synergistic effects of IH with cigarette smoke-induced emphysema produce a greater inflammatory status and endothelial apoptosis. OS-related inflammation and endothelial cell apoptosis may play important roles in promoting cardiovascular dysfunction, and antioxidant tempol could achieve a partial protective effect.

• Journal of Ginseng Research
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• v.47 no.1
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• pp.144-154
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• 2023

Background: As the major pathophysiological feature of obstructive sleep apnea (OSA), chronic intermittent hypoxia (CIH) is vital for the occurrence of cardiovascular complications. The activation of calpain-1 mediates the production of endothelial reactive oxygen species (ROS) and impairs nitric oxide (NO) bioavailability, resulting in vascular endothelial dysfunction (VED). Ginsenoside Rg1 is thought to against endothelial cell dysfunction, but the potential mechanism of CIH-induced VED remains unclear. Methods: C57BL/6 mice and human coronary artery endothelial cells (HCAECs) were exposed to CIH following knockout or overexpression of calpain-1. The effect of ginsenoside Rg1 on VED, oxidative stress, mitochondrial dysfunction, and the expression levels of calpain-1, PP2A and p-eNOS were detected both in vivo and in vitro. Results: CIH promoted VED, oxidative stress and mitochondrial dysfunction accompanied by enhanced levels of calpain-1 and PP2A and reduced levels of p-eNOS in mice and cellular levels. Ginsenoside Rg1, calpain-1 knockout, OKA, NAC and TEMPOL treatment protected against CIH-induced VED, oxidative stress and mitochondrial dysfunction, which is likely concomitant with the downregulated protein expression of calpain-1 and PP2A and the upregulation of p-eNOS in mice and cellular levels. Calpain-1 overexpression increased the expression of PP2A, reduced the level of p-eNOS, and accelerated the occurrence and development of VED, oxidative stress and mitochondrial dysfunction in HCAECs exposed to CIH. Moreover, scavengers of O₂^·-, H₂O₂, complex I or mitoKATP abolished CIH-induced impairment in endothelial-dependent relaxation. Conclusion: Ginsenoside Rg1 may alleviate CIH-induced vascular endothelial dysfunction by suppressing the formation of mitochondrial reactive oxygen species through the calpain-1 pathway.

• Neonatal Medicine
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• v.17 no.1
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• pp.44-52
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• 2010

Purpose : The aim of this study was to develop a model for necrotizing enterocolitis (NEC) in the neonatal rat using endotoxin and hypoxia, a plausible insult in a neonatal intensive care and to investigate the role of apoptosis as the underlying mechanism. Methods : Newborn rats were given oral endotoxin and intermittent 8% hypoxia$\pm$caspase inhibitor. The intestinal histology was evaluated using hematoxylin-eosin staining. Apoptosis was analyzed with TUNEL staining and by measuring the caspase 3 activity in the intestinal lysates. IEC-6 cells were assessed for apoptosis and the expression of Bax, Bcl-2, Fas and FasL was measured after treatment with endotoxin and hypoxia. Results : Oral endotoxin (5 mg/kg) and exposure to 8% hypoxia of 60-min duration twice induced human NEC-like lesions in the rat intestine. Intestinal tissue revealed increased apoptosis and caspase-3 activity. After caspase inhibitor treatment, the grades of both apoptosis and NEC were significantly reduced. IEC-6 cells exhibited increased apoptosis and caspase 3 activity after endotoxin and hypoxia treatment and significantly increased Bax/Bcl- 2 ratio compared to control cells. Conclusion : This neonatal rat model of NEC which was induced by oral endotoxin and intermittent hypoxia showed increased apoptosis of intestinal epithelial cells that was mediated by caspase 3 activation. Our model has a advantage in the study of NEC because the use of much more clinically plausible insults may provide a suitable model for the investigation of its pathophysiology and therapeutic trials.

• Journal of Oral Medicine and Pain
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• v.43 no.3
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• pp.61-69
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• 2018

Obstructive sleep apnea (OSA) is a relatively common, but greatly underdiagnosed sleep-related breathing disorder, characterized by recurrent collapse of the upper airway during sleep. OSA has been associated with a variety of cardiometabolic disease, such as hypertension, coronary artery disease, cardiac arrhythmia, cerebrovascular disease and metabolic dysfunction. Neurocognitive impairment, including excessive daytime sleepiness, increased risk of motor vehicle accidents, is also related to OSA. Sleep fragmentation and related arousals during sleep lead to intermittent hypoxia, sympathetic activation, oxidative stress, systemic inflammation and metabolic dysregulation which provide biological plausibility to this pathologic mechanism. Extensive studies demonstrated that OSA is a modifiable risk factor for the above mentioned diseases and oral appliances (OAs), although continuous positive air pressure (CPAP) is a first-line therapy of OSA, are not inferior to CPAP at least in mild OSA, and may be an alternative to CPAP in CPAP-intolerant subjects with OSA. The goal of this article is to provide a current knowledge of pathologic link between OSA and cardiovascular disease, focusing on intermittent hypoxia, sympathetic activation, oxidative stress and metabolic dysregulation. Then, previous epidemiologic studies will be reviewed to understand the causal relationship between OSA and cardiovascular disease. Finally, the effects of OAs will be updated via recent metaanalyses compared to CPAP.

• Toxicological Research
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• v.15 no.1
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• pp.27-34
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• 1999

To study the nature of differentially manifested adaptive response of an organism according to the intensities of the stress, the immune effects of different levels of repeated hypoxia were investigated. Four experimental groups (NH : not -handled, 20% : handled, 15% or 10% : exposed to 15% or 10% $\textrm{O}_2$ 씨오투 with balanced nitrogen, respectively) of mice were exposed to different levels of hypoxia for 60 min/day, 5days/week in a repeated and intermittent manner. After 8 weeks' exposure to hypoxia environment, mice were subjected to immune function measurements, A decreased proportion of CD3+ CD8 phenotype cells in the study of splenocyte subsets was observed in the 10% group. Ovalbumin-stimulated IgG2a production was increased in the 15% group, while no changes were noted in the IgGl and IgM production. No significant changes of the antigen-stimulated splenocyte proliferation and the natural killer cell cytotoxicity were found. These results show that the stress effects on the immune systems can be varied according to the strength of the stress and that a mild level of repeated hypoxic stress can enhance the immune function of mice in this experimental model.

• Sleep Medicine and Psychophysiology
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• v.20 no.1
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• pp.10-14
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• 2013

Sleep disturbances are commonly encountered problems in cancer patients. Sleep has a role in maintenance of immunity, metabolism, and quality of life but little has been known about the prevalence, risk factors, and effects on prognosis of sleep disturbances in patients with cancer. Also little attention has been made on proper assessment and management of sleep disorders in these patients. Recently, there have been some reports that sleep disorders are related with development of many cancers such as breast, colorectal, prostate, and endometrial cancers. An intermittent hypoxia and a disruption of circadian rhythm are considered as one of the possible mechanisms of cancer developments. More aggressive evaluation and meticulous management of sleep disturbances in cancer patients are essential to improve quality of life as well as prognosis.

• The Korean Journal of Physiology and Pharmacology
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• v.28 no.5
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• pp.469-478
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• 2024

Chronic intermittent hypoxia (CIH) can lead to vascular dysfunction and increase the risk of cardiovascular diseases, cerebrovascular diseases, and arterial diseases. Nevertheless, mechanisms underlying CIH-induced vascular dysfunction remain unclear. Herein, this study analyzed the role of aortic smooth muscle calcium-activated potassium (BK) channels in CIH-induced vascular dysfunction. CIH models were established in rats and rat aortic smooth muscle cells (RASMCs). Hemodynamic parameters such as mean blood pressure (MBP), diastolic blood pressure (DBP), and systolic blood pressure (SBP) were measured in rats, along with an assessment of vascular tone. NO and ET-1 levels were detected in rat serum, and the levels of ET-1, NO, eNOS, p-eNOS, oxidative stress markers (ROS and MDA), and inflammatory factors (IL-6 and TNF-α) were tested in aortic tissues. The Ca²⁺ concentration in RASMCs was investigated. The activity of BK channels (BKα and BKβ) was evaluated in aortic tissues and RASMCs. SBP, DBP, and MBP were elevated in CIH-treated rats, along with endothelial dysfunction, cellular edema and partial detachment of endothelial cells. BK channel activity was decreased in CIH-treated rats and RASMCs. BK channel activation increased eNOS, p-eNOS, and NO levels while lowering ET-1, ROS, MDA, IL-6, and TNF-α levels in CIH-treated rats. Ca²⁺ concentration increased in RASMCs following CIH modeling, which was reversed by BK channel activation. BK channel inhibitor (Iberiotoxin) exacerbated CIH-induced vascular disorders and endothelial dysfunction. BK channel activation promoted vasorelaxation while suppressing vascular endothelial dysfunction, inflammation, and oxidative stress, thereby indirectly improving CIH-induced vascular dysfunction.

• Journal of fish pathology
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• v.36 no.2
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• pp.379-388
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• 2023

Experiments were performed to investigate hypoxia tolerance with body size of red seabream (Pagrus major) at 24℃. The rate of oxygen consumption was measured at an interval of 10 min using automated intermittent-flow respirometry. The weight-specific standard metabolic rate (SMR, mg O₂ kg^-1hr^-1) and critical oxygen saturation (S_crit, % air saturation) of the fish were measured under normoxic condition and progressive hypoxia with 0.6-786 g of fish weight (W), respectively. SMR typically decreased with increasing body weight based on SMR=351.59·W^-0.195 (r²=0.934). S_crit was higher in larger fish than those of smaller fish in the range of 17.3-24.4%. The result of this study suggests that the smaller seabream can withstand in hypoxic waters better than the larger ones.