慢性间歇低氧对大鼠血压和交感神经兴奋性的影响

目的 通过观察不同程度慢性间歇低氧(chronic intermittent hypoxia,CIH)作用下大鼠血压与交感神经活性水平动态变化,探讨CIH对血压及交感神经活性的影响及血压与交感神经活性之间的相关性,并明确CIH诱发高血压发病的机制.方法 168只雄性6周龄Wistar大鼠,体重160 ～ 180 g,采用随机数字表法分为非暴露组(UD)、重度间歇低氧组(IH1)、中度间歇低氧组(IH2)、轻度间歇低氧组(IH3)、持续低氧组(CH)及对照组,分别给予不同程度和频率的低氧环境.UD组8只大鼠于实验前处死,其余各实验组每组32只大鼠,分别于2、4、6、8周时随机抽取8只处死,留取静脉血抗凝离心后- 80℃保存血浆,并于实验前、实验结束后分别测定动脉收缩压,实验结束后测定血浆中去甲肾上腺素(norepinephrine,NE).结果 各组大鼠实验前收缩压差异无统计学意义(F=0.008,P＞0.05),随着实验时间延长,各间歇低氧组大鼠收缩压逐渐升高,4周开始明显高于UD组、对照组及CH组(均P＜0.05)且血压水平与低氧程度正相关(F =9.844,P＜0.01),IH1组明显高于IH3组(P＜0.05),而对照组和CH组无明显改变.各间歇低氧组大鼠血浆NE随实验时间延长而逐渐升高,8周时明显高于UD组、SC组及CH组(均P＜0.05或P＜0.01),且NE水平与低氧程度正相关(F=11.537,P＜0.01),IH1组明显高于IH3组(P＜0.05),SC组和CH组大鼠血浆NE变化不显著.大鼠血浆NE与血压呈显著正相关(r=0.538,P＜0.01).结论 CIH作用可以引起大鼠血压增高和交感活性增强且存在明显的低氧程度依赖性和时间过程规律性,推测CIH引起大鼠血压增高可能与交感活性增强相关.     

模拟慢性间歇低氧对大鼠左心室心肌力学的影响

睡眠期间反复短暂缺氧是阻塞性睡眠呼吸暂停低通气综合征 (OSAHS)患者的主要发病特点。我们模拟OSAHS患者的低氧特点 ,观察慢性间歇低氧对大鼠左心室功能的影响。材料与方法　雄性Wistar大鼠 30只 (中国军事医学科学院实验动物所提供 ) ,体重 2 5 0～ 30 0g ,采用随机排列表法分为间歇低氧组 (IH组 )、实验对照组 (SC组 )和空白对照组(UC组 ) ,每组 10只。将IH组和SC组的大鼠分别置于 2个相同的有机玻璃舱内 ,每天 8h ,共 6周。IH组的舱内循环充入氮气和压缩空气 ,每一循环 6 0s,即 30s充入氮气 ,随之 30s充入压缩空气 ,并调节气…     

不同频率间歇低氧下大鼠肝脏氧化应激损伤及Tempol的干预作用

目的 探讨不同频率间歇低氧(IH)对大鼠肝脏氧化应激损伤差异和Tempol的干预作用及可能机制.方法 应用慢性间歇低氧(CIH)大鼠模型,模拟OSAS周期性间歇低氧/再氧和病理生理过程.56只雄性Wistar大鼠随机分为不同频率IH组(IH1,IH2,IH3,IH4,频率依次为10、20、30、40次/h),30T组(...     

慢性间歇低氧诱发大鼠高血压发病过程中一氧化氮和一氧化氮合酶的变化

目的:观察慢性间歇低氧诱发大鼠高血压发病过程中一氧化氮(NO)和一氧化氮合酶(NOS)的动态变化,探讨慢性间歇低氧诱发高血压的发病机制。方法:将Wistar大鼠(72只)随机分为间歇低氧组(IH组)、实验对照组(SC组)和空白对照组(UC组);IH组大鼠循环给予氮气和压缩空气(每一循环60s,使舱内最低氧浓度达4%~6%,然后恢复至21%,8h/d),SC组大鼠循环给予压缩空气,UC组大鼠不予任何处理。观察第8、22、43天时各组大鼠血压、血浆NO水平和NOS活性以及不同组织内皮型一氧化氮合酶(eNOS)mRNA的表达。结果:第43天时IH组大鼠平均动脉压(MAP)较实验前升高约8mmHg[(1mmHg=0.133kPa)(P<0.01)],而两对照组大鼠MAP无显著变化。IH组大鼠血浆NO水平和NOS活性随间歇低氧时间的延长逐渐下降,NO水平从第22天[(31.9±9.3)μmol/L]开始显著低于SC[(49.4±10.3)μmol/L]和UC组[(47.8±11.5)μmol/L](P均<0.01),NOS活性也从第22天[(18.1±4.5)U/ml]开始显著低于SC[(22.5±4.0)U/ml](P<0.05)和UC组[(25.6±4.0)U/ml](P<0.01),并且血浆NO水平和NOS活性与MAP均呈负相关(r=-0.566,P<0.01和r=-0.454,P<0.05);其主动脉、心脏和肾皮质eNOSmRNA的表达在第43天时均显著低于两对照组水平(均P<0.05)。SC组与UC组大鼠比较,各项观察指标差异均无统计学意义(P>0.05)。结论:慢性间歇低氧可引起eNOS表达下降和NOS活性降低,使NO合成释放减少,可能是慢性间歇低氧诱发高血压的重要原因之一。     

不同程度、频率、时限的间歇低氧细胞模型

目的阐述建立不同间歇低氧程度、频率、以及低氧时限细胞模型的过程,并论述这一模型的科学性。方法由计算机程序控制单片机及电磁阀,继而控制预混气源系统气流的通/断,在细胞培养舱中模拟不同程度、频率、以及时限的间歇低氧/再氧合暴露条件。结果培养舱气体相的暴露水平就是预设的暴露条件,而在一般间歇低氧/再氧合循环时,ECV 304细胞实际PO2和PCO2暴露条件为(76.28±1.2930)mmHg~(54.94±1.0502)mmHg和(38.26±1.4943)mmHg~(88.64±1.5027)mmHg。结论本模型基本上可以模拟出阻塞性睡眠呼吸暂停的间歇低氧以及其不同间歇低氧程度、频率、时限的细胞暴露水平,在一定程度上可以满足实验的需要。     

交感神经兴奋在慢性间歇性低氧引起高血压发生过程中的作用

交感神经活性增强在阻塞性睡眠呼吸暂停引起的高血压及其他心血管疾病发生过程中起到重要作用.阻塞性睡眠呼吸暂停(obstructive sleep apnea,OSA)最为明显的特征就是夜间反复的间歇 性低氧,这种间歇性低氧状态对于交感神经激活及血压升高显得尤为重要.以下就OSA相关性间歇性低氧引起的交感神经系统激活以及其...     

血管紧张素Ⅱ及其受体在慢性间歇低氧诱发大鼠高血压发病过程中的动态变化

目的　观察慢性间歇低氧诱发大鼠高血压发病过程中血管紧张素Ⅱ (ATⅡ )及其受体的动态变化 ,并探讨其在慢性间歇低氧诱发高血压发病机制中的作用。方法　 72只雄性Wistar大鼠随机均分为间歇低氧组 (IH组 )、实验对照组 (SC组 )和空白对照组 (UC组 ) ;IH组大鼠循环给予氮气和压缩空气 (每一循环 6 0s,使舱内最低氧浓度达 4 %～ 6 % ,然后恢复至 2 1% ,8h/d) ,SC组大鼠循环给予压缩空气 ,UC组大鼠不予任何处理。观察第 7、2 1、4 2天时各组大鼠血压、血浆肾素活性 (RA)和ATⅡ水平以及不同组织ATⅡ 1型受体 (AT1R)mRNA的表达。结果　第 4 2天时IH组大鼠平均动脉压(MAP)为 (10 2 2± 6 2 )mmHg(1mmHg =0 133kPa) ,显著高于SC组 [(95 7± 3 6 )mmHg]、UC组 [(97 2±3 6 )mmHg ,P均 <0 0 5 ]和实验前水平 [(94 1± 4 3)mmHg ,P <0 0 1];IH组大鼠血浆RA从第 7天[(3 86± 1 2 5 )ng·ml-1·h-1]开始显著高于SC[(2 73± 0 98)ng·ml-1·h-1]、UC组 [(2 5 5± 0 87)ng·ml-1·h-1,P均 <0 0 5 ],血浆ATⅡ从第 2 1天 [(2 14± 4 1)ng/L]开始显著高于SC[(12 4± 2 1)ng/L]、UC组 [(12 1± 18)ng/L ,P均 <0 0 1];并且血浆RA和ATⅡ水平与MAP均呈正相关 (r =0 5 2 9,P =0 0 0 8和r=0 4 75 ,P =0 0 19     

间歇低氧对人脐静脉内皮细胞中内皮素的影响

目的通过建立间歇低氧细胞模型,测定不同低氧模式下人脐静脉内皮细胞中内皮素(endothelin,ET)含量的变化,以进一步探讨ET在细胞水平对间歇低氧在阻塞性睡眠呼吸暂停综合征合并高血压患者中的作用.方法采用人脐静脉内皮细胞可传代细胞株ECV304细胞系,暴露于不同低氧条件,暴露完成后采用双抗夹心酶联免疫吸附法(ELISA法)测定培养基中ET浓度.结果间歇低氧组ET浓度[(12.86±6.68)pg/mL]与间歇正常氧组[(3.29±0.88)pg/mL]及空白对照组[(4.67±1.22)pg/mL]间差异有统计学意义(F=13.687,P<0.05).其中,间歇低氧组高于间歇正常氧组(P<0.05)及空白对照组(P<0.05),而间歇正常氧组及空白对照组间差异无统计学意义(P>0.05).相同累加低氧时间及程度的间歇低氧组ET浓度显著高于持续低氧组[(7.07±1.00)pg/mL](P<0.05).结论间歇低氧可引起ET水平升高,提示ET在间歇低氧合并高血压中可能起重要作用.     

不同程度间歇低氧对大鼠血清炎性细胞因子白介素8、白介素10的影响

目的 探讨不同程度间歇低氧对大鼠血清炎性细胞因子白介素8(IL-8)和抗炎细胞因子IL-10水平的影响.方法 160只雄性Wistar大鼠随机分为5组:5%,7.5%,10%间歇低氧组,10%持续低氧对照组和常氧对照组各32只,分别于低氧暴露第2周、第4周、第6周和第8周每组随机抽取8只大鼠,应用酶联免疫吸附试验法检...     

慢性间歇低氧对大鼠肾脏组织细胞形态和超微结构的影响

目的 探讨慢性间歇低氧( CIH)对肾脏组织细胞形态和超微结构的影响及其意义.方法 采用自制的CIH动物舱,通过控制程序调节舱内氧气、氮气的输入流量,使得每1次缺氧循环时间为1 min,氧气浓度循环于7％～21％之间.将18只大鼠随机分成2组,每组9只,分别为对照组和CIH组.将CIH组置于动物舱给予间歇缺氧,每天8h,持续35 d.对照组动物舱内输入空气,其余条件同CIH组.HE染色观察肾脏组织细胞形态,透射电镜观察肾近曲小管上皮细胞超微结构.结果 HE染色示对照组肾脏组织形态基本正常,CIH组肾小球高度肿胀,肾球囊狭窄,近曲小管上皮细胞高度肿胀,管腔狭窄.透射电镜观察发现对照组肾脏超微结构基本正常,CIH组肾近曲小管上皮细胞出现空泡变性、核膜肿胀和线粒体肿胀.结论 CIH导致肾脏组织细胞水肿变性和超微结构异常,可能与OSAHS引起肾脏损害有关.     

Melatonin ameliorates endothelial dysfunction,vascular inflammation,and systemic hypertension in rats with chronic intermittent hypoxia

The pathogenesis of hypertension in patients with obstructive sleep apnea (OSA) is associated with endothelial dysfunction induced by chronic intermittent hypoxia (IH). Studies have shown that administration of melatonin ameliorates oxidative injury and inflammation. This study examined the effect of melatonin on the oxidative stress, endothelial dysfunction, and inflammation during the pathogenesis of hypertension in chronic IH. Adult Sprague‐Dawley rats that had received a daily injection of melatonin or vehicle were exposed to IH treatment mimicking a severe OSA condition for 14–21 days. Systolic pressure was significantly higher in the vehicle‐treated (144 ± 2.7 mmHg) but not in the melatonin‐treated rats (123 ± 5.1 mmHg) by 21–day IH treatment when compared with the normoxic control. Levels of malondialdehyde and the expressions of NADPH oxidase, pro‐inflammatory mediators (TNF‐α, inducible NO synthase, COX‐2), and adhesion molecules (ICAM‐1, VCAM‐1, and E‐selectin) of the thoracic aorta were markedly increased by 14‐day IH treatment preceding the hypertensive response. Also, levels of nitric oxide (NO˙), endothelial‐dependent relaxation, and the expressions of endothelial NO synthase (eNOS) and antioxidant enzymes (GPx, CAT, and Cu/Zn SOD) were significantly lowered in the IH rats. Melatonin treatment significantly mitigated the increased expression of NADPH oxidase, pro‐inflammatory mediators, and adhesion molecules. Moreover, melatonin prevented the endothelial dysfunction with ameliorated levels of NO˙, endothelial‐dependent relaxation, and expressions of eNOS and antioxidant enzymes. These results suggest that melatonin is protective against IH‐induced hypertension and endothelial dysfunction via an antioxidant and anti‐inflammatory mechanism.     

阻塞性睡眠呼吸暂停低通气综合征合并高血压的机制研究

多项研究提示阻塞性睡眠呼吸暂停低通气综合征是高血压发病的独立危险因素.应激、氧化应激、系统性炎症、代谢紊乱、睡眠结构改变及遗传易感性等多种机制可能参与阻塞性睡眠低通气综合征并高血压的发生、发展.     

慢性间歇低氧诱导小鼠学习记忆障碍的实验研究

目的 探讨慢性间歇低氧（CIH）诱导小鼠空间学习记忆能力的变化及CIH对认知功能损伤的可能机制.方法 60只ICR雄性幼鼠随机分为常氧对照组（UC组）和间歇低氧组（CIH组）,每组30只;CIH组小鼠置于低氧舱内,通过吹入氮气及压缩空气,每60s做一次缺氧/再氧合循环,使氧浓度波动在6％～8％和20％～ 21％之间,每天8h.CIH组根据低氧造模时间分为3d（A组）、1周（B组）、2周（C组）、4周（E组）、6周（F组）,以及造模结束后常氧饲养1月的10周组（G组）,共6组,每组5只小鼠,同期设6组对照,每组5只小鼠.在慢性间歇低氧3d、1周、2周及6周终点,采用Morris水迷宫的方法测定CIH组和UC组空间学习记忆功能的变化;Western blot法分别测各组海马N-甲基-D-天冬氨酸受体（NMDAR）亚单位1（NR1）蛋白表达的变化;采用免疫荧光标记测定海马Caspase-3表达情况.结果 ①CIH组小鼠在间歇低氧3d时,水迷宫逃避潜伏期较对照组有所延长,但无统计学差异（P＞0.05）;随着间歇低氧时间的延长,逃避潜伏期较对照组逐渐延长（P＜0.05）;低氧6周后,CIH组逃避潜伏期[（68.64±26.52）s]较对照组[（21.36±14.14）s]明显延长（P＜0.01）.低氧6周后,CIH组穿越平台次数[（4.58±2.58）次]较对照组[（8.06±2.74）次]明显减少（P＜0.01）;②与对照组比较,CIH组B、C、E、F及G组小鼠海马神经元NR1蛋白表达均降低（P＜0.叭）,C、E组降至最低水平（P＜0.01）;复氧1月后的G组NR1蛋白与F组相仿,仍较对照组降低（P＜0.01）.CIH各组海马Caspase-3表达均明显升高,并成时间-效应关系,除A组外,其余各组与对照组相比,差异均有统计学意义（P均＜0.01）,CIH组组内指标比较无显著差异（P＞0.05）.结论 慢性间歇低氧诱导小鼠空间学习记忆障碍,且随低氧暴露时间延长学习记忆功能损害加重,这可能与海马神经元NR1蛋白表达下调以及与Caspase-3介导的海?     

交感神经活性和血管内皮功能在阻塞性睡眠呼吸暂停低通气综合征合并高血压发病机制中的作用

目的探讨交感神经活性、血管内皮功能在阻塞性睡眠呼吸暂停低通气综合征（OSAHS）合并高血压发病机制中的作用。方法根据整夜多导睡眠监测（PSG）、血压测量和病史采集将93例患者分为：OSAHS血压正常组、OSAHS合并高血压组、高血压不合并OSAHS组和健康对照组。测定PSG当晚睡眠前后血压、血浆去甲肾上腺素、血浆内皮素和血清一氧化氮；收集PSG当晚22点至次晨6点的所有尿液送检尿3-甲氨基4-羟苦杏仁酸（VMA）。结果OSAHS组患者不论有无高血压，各指标变化为：晨起血浆去甲肾上腺素均显著高于睡前，OSAHS合并高血压组升高更明显；醒后去甲肾上腺素与醒后平均动脉压、睡眠呼吸暂停低通气指数（AHI）、氧减次数、氧减指数、睡眠期间血氧饱和度低于90％的时间占总睡眠时间的百分比（T90）呈显著正相关，与睡眠时最低血氧饱和度（minSaO2）和夜间平均血氧饱和度（MSaO2）呈显著负相关；醒后内皮素显著增高、一氧化氮明显下降，而另外两组则相反；醒后内皮素与醒后平均动脉压、AHI、最长呼吸暂停时间、呼吸暂停总时间、氧减次数、氧减指数、T90呈显著正相关，与minSaO2、MSaO2呈显著负相关；醒后一氧化氮与醒后平均动脉压、AHI、最长呼吸暂停时间、呼吸暂停总时间、氧减次数、氧减指数、T90呈显著负相关。与minSaO2、MSaO2呈显著正相关。各组间尿VMA无明显变化。结论在OSAHS患者夜间一过性血压升高和持续性高血压形成方面，交感神经系统活性增强、血管内皮功能紊乱导致的内皮源性舒、缩因子失衡可能起着重要的作用。     

Cardioprotective effects of melatonin against myocardial injuries induced by chronic intermittent hypoxia in rats

Obstructive sleep apnea (OSA) associated with chronic intermittent hypoxia (CIH) increases the morbidity and mortality of ischemic heart disease in patients. Yet, there is a paucity of preventive measures targeting the pathogenesis of CIH‐induced myocardial injury. We examined the cardioprotective effect of melatonin against the inflammation, fibrosis and the deteriorated sarcoplasmic reticulum (SR) Ca²⁺ homeostasis, and ischemia/reperfusion (I/R)‐induced injury exacerbated by CIH. Adult male Sprague Dawley rats that had received a daily injection of melatonin (10 mg/kg) or vehicle were exposed to CIH treatment mimicking a severe OSA condition for 4 wk. Systolic pressure, heart weights, and malondialdehyde were significantly increased in hypoxic rats but not in the melatonin‐treated group, when compared with the normoxic control. Levels of the expression of inflammatory cytokines (TNF‐α, IL‐6, and COX‐2) and fibrotic markers (PC1 and TGF‐β) were significantly elevated in the hypoxic group but were normalized by melatonin. Additionally, infarct size of isolated hearts with regional I/R was substantial in the hypoxic group treated with vehicle but not in the melatonin‐treated group. Moreover, melatonin treatment mitigated the SR‐Ca²⁺ homeostasis in the cardiomyocyte during I/R with (i) Ca²⁺ overloading, (ii) decreased SR‐Ca²⁺ content, (iii) lowered expression and activity of Ca²⁺‐handling proteins (SERCA2a and NCX1),and (iv) decreased expressions of CAMKII and phosphorylated eNOS^ser1177. Furthermore, melatonin ameliorated the level of expression of antioxidant enzymes (CAT and MnSOD) and NADPH oxidase (p22 and NOX2). Results support a prophylactic usage of melatonin in OSA patients, which protects against CIH‐induced myocardial inflammation and fibrosis with impaired SR‐Ca²⁺ handling and exacerbated I/R injury.     

Effects of various degrees of oxidative stress induced by intermittent hypoxia in rat myocardial tissues

Background and objective: The aim of this study was to investigate the mechanism by which oxidative stress induced by chronic intermittent hypoxia (IH) causes myocardial damage in obstructive sleep apnoea syndrome. Methods: A total of 160 Wistar rats were divided into five experimental groups and subjected to chronic IH with different concentrations of oxygen (5%, 7.5%, 10% IH groups; 10% continuous oxygen and normoxia control groups). Eight rats from each group were sacrificed at the 2‐, 4‐, 6‐ and 8‐week time points. Superoxide dismutase (SOD) activity, malondialdehyde (MDA) levels and total anti‐oxidant capability (T‐AOC) were measured in supernatants of heart homogenates. Expression of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, p22^phox and NOX2, and thioredoxin‐2 (Trx‐2) genes were determined by measuring messenger RNA (mRNA) levels by real‐time polymerase chain reaction. Results: Compared with the control groups, MDA levels increased over time in the IH groups, whereas T‐AOC and SOD activity decreased over time. MDA, T‐AOC and SOD activity peaked at 6 weeks into the IH treatment. The 5% IH group showed significantly higher expression of p22^phox and thioredoxin‐2 mRNA, as compared with the other IH groups, as well as the control groups. Conclusions: The severity of oxidative stress induced by chronic IH in myocardial tissue was significantly correlated with the degree of IH. NADPH oxidase and Trx‐2 are important mediators of oxidative stress induced by IH.