Effects of chronic episodic hypoxia on rat upper airway muscle contractile properties and fiber-type distribution

OBJECTIVE: Contraction of upper airway (UA) muscles such as the geniohyoids and sternohyoids dilates and/or stabilizes the UA, thereby maintaining its patency. Obstructive sleep apnea (OSA) is caused by episodes of UA collapse, and this results in chronic episodic hypoxia. Chronic continuous hypoxia affects skeletal muscle structure and function, but the effects of chronic episodic hypoxia on UA muscle structure and function are unknown. DESIGN: Rats were exposed to alternating periods of hypoxia and normoxia twice per minute for 8 h/d for 5 weeks in order to mimic the intermittent hypoxia of OSA in humans. Isometric contractile properties were determined using strips of isolated geniohyoid and sternohyoid muscles in physiologic saline solution at 30 degrees C. Fiber-type distribution was determined using adenosine triphosphatase staining. RESULTS: Chronic episodic hypoxia had no significant effect on twitch or tetanic tension, twitch/tetanic tension ratio, contractile kinetics, tension-frequency relationship, or fiber-type distribution for either the sternohyoid or geniohyoid muscle. However, chronic episodic hypoxia did significantly increase sternohyoid and geniohyoid fatigue and reduced recovery from fatigue. CONCLUSIONS: Chronic episodic hypoxia increases UA muscle fatigue, an effect that may compromise the maintenance of UA patency.     

Chronic intermittent hypoxia predisposes to liver injury

Obstructive sleep apnea (OSA) is characterized by chronic intermittent hypoxia (CIH). OSA is associated with nonalcoholic steatohepatitis (NASH) in obese subjects. The aim of this study was to investigate the effects of CIH on the liver in the absence of obesity. Lean C57BL/6J mice (n = 15) on a regular chow diet were exposed to CIH for 12 weeks and compared with pair-fed mice exposed to intermittent air (IA, n = 15). CIH caused liver injury with an increase in serum ALT (224 +/- 39 U/l versus 118 +/- 22 U/l in the IA group, P < 0.05), whereas AST and alkaline phosphatase were unchanged. CIH also induced hyperglycemia, a decrease in fasting serum insulin levels, and mild elevation of fasting serum total cholesterol and triglycerides (TG). Liver TG content was unchanged, whereas cholesterol content was decreased. Histology showed swelling of hepatocytes, no evidence of hepatic steatosis, and marked accumulation of glycogen in hepatocytes. CIH led to lipid peroxidation of liver tissue with a malondialdehyde (MDA)/free fatty acids (FFA) ratio of 0.54 +/- 0.07 mmol/mol versus 0.30 +/- 0.01 mmol/mol in control animals (P < 0.01), and increased levels of active nuclear factor kappaB (NF-kappaB) in the nuclear fraction of hepatocytes, suggesting that CIH induced oxidative stress in the liver. Finally, CIH greatly exacerbated acetaminophen-induced liver toxicity, causing fulminant hepatocellular injury. CONCLUSION: In the absence of obesity, CIH leads to mild liver injury via oxidative stress and excessive glycogen accumulation in hepatocytes and sensitizes the liver to a second insult, whereas NASH does not develop.     

Effects of chronic intermittent asphyxia on rat diaphragm and limb muscle contractility

OBJECTIVE: In obstructive sleep apnea (OSA), there is intermittent upper airway (UA) collapse due to an imbalance between the collapsing force generated by the diaphragm and the stabilizing force of the UA muscles. This results in chronic intermittent asphyxia (CIA). We have previously shown that CIA affects UA muscle fatigue, but little is known about the effects of chronic hypoxia on diaphragm or on limb muscle contractile properties and structure. DESIGN: Rats were exposed to asphyxia and normoxia twice per minute for 8 h/d for 5 weeks to simulate the intermittent asphyxia of OSA in humans. Isometric contractile properties were determined from strips of isolated diaphragm, extensor digitorum longus (EDL), and soleus muscles in Krebs solution at 30 degrees C. EDL and soleus type 1 (slow, fatigue resistant), type 2A (fast, fatigue resistant), and type 2B (fast, fatigable) fiber distribution was determined using adenosine triphosphatase staining. RESULTS: CIA caused a significant increase in diaphragm, EDL, and soleus fatigue, and reduced recovery from fatigue. Most of the other contractile properties were unaffected aside from a small reduction in diaphragm half-relaxation time and EDL twitch tension and a small shift to the left in the EDL force-frequency curve. There was no change in soleus fiber-type distribution and a small increase in EDL type 2A fibers (46.1 +/- 1.2% vs 49.9 +/- 1.4%, control vs CIA [mean +/- SD]). CONCLUSIONS: CIA increases diaphragm, EDL, and soleus muscle fatigue. We speculate that if this also occurs in OSA, it would contribute to the pathophysiology of the condition.     

慢性间歇低氧与氧化应激

慢性间歇低氧(Chronic intermittent hypoxia,CIH)是睡眠呼吸暂停的重要病理生理机制,是造成OSAHS患者心血管系统以及其他脏器损害的基础.与广义的间歇低氧不同,睡眠呼吸暂停模式的CIH具有如下特点:正常氧和低氧交替出现,不管低氧程度多么严重,低氧解除后都会恢复到正常氧水平.低氧发生的频率很高,一般在5～100次/h,平均每1～5 min发生1次.低氧程度严重,血氧变化幅度大,最低动脉氧饱和度可降低到20%或更低,正常氧与低氧间动脉血氧饱和度之差可达30%～70%[1].此过程类似缺血再灌注损伤,可引起氧化应激反应,成为睡眠呼吸暂停靶器官损伤的重要机制.     

The effects of chronic episodic hypercapnic hypoxia on rat upper airway muscle contractile properties and fiber-type distribution

OBJECTIVE: Obstructive sleep apnea (OSA) is caused by episodes of upper airway (UA) obstruction due to an inability of UA muscles such as the geniohyoids and sternohyoids to maintain airway patency. This results in chronic episodic hypercapnic hypoxia. Chronic continuous hypoxia and episodic hypocapnic hypoxia affect skeletal muscle structure and function, but the effects of chronic episodic hypercapnic hypoxia on UA muscle structure and function are unknown. DESIGN: Rats breathed air and hypercapnic hypoxic gas twice per minute for 8 h/d for 5 weeks in order to mimic the intermittent hypercapnic hypoxia of OSA in humans. Isometric contractile properties were determined using strips of isolated geniohyoid and sternohyoid muscles in physiologic saline solution at 30 degrees C. Fiber-type distribution was determined by adenosine triphosphatase staining. RESULTS: For both muscles, chronic episodic hypercapnic hypoxia had no significant effect on twitch or tetanic tension, twitch/tetanic tension ratio, and tension-frequency relationship. There was a significant (p < 0.05) increase in geniohyoid fatigue (50.5 +/- 6.6% vs 43.6 +/- 5.8% of initial tension), but sternohyoid fatigue was reduced (31.5 +/- 5.2% vs 37.8 +/- 6.0% of initial tension). Geniohyoid type 1 fibers were reduced and type 2B fibers increased, whereas sternohyoid muscle had an increase in type 1 and 2A fibers and a decrease in type 2B fibers. CONCLUSIONS: Chronic episodic hypercapnic hypoxia alters UA muscle structure and function, changes that may affect the regulation of UA patency.     

Chronic intermittent hypoxia induces atherosclerosis

RATIONALE: Obstructive sleep apnea, a condition leading to chronic intermittent hypoxia (CIH), is associated with hyperlipidemia, atherosclerosis, and a high cardiovascular risk. A causal link between obstructive sleep apnea and atherosclerosis has not been established. OBJECTIVES: The objective of the present study was to examine whether CIH may induce atherosclerosis in C57BL/6J mice. METHODS: Forty male C57BL/6J mice, 8 weeks of age, were fed either a high-cholesterol diet or a regular chow diet and subjected either to CIH or intermittent air (control conditions) for 12 weeks. MEASUREMENTS AND MAIN RESULTS: Nine of 10 mice simultaneously exposed to CIH and high-cholesterol diet developed atherosclerotic lesions in the aortic origin and descending aorta. In contrast, atherosclerosis was not observed in mice exposed to intermittent air and a high-cholesterol diet or in mice exposed to CIH and a regular diet. A high-cholesterol diet resulted in significant increases in serum total and low-density lipoprotein cholesterol levels and a decrease in high-density lipoprotein cholesterol. Compared with mice exposed to intermittent air and a high-cholesterol diet, combined exposure to CIH and a high-cholesterol diet resulted in marked progression of dyslipidemia with further increases in serum total cholesterol and low-density lipoprotein cholesterol (124 +/- 4 vs. 106 +/- 6 mg/dl; p < 0.05), a twofold increase in serum lipid peroxidation, and up-regulation of an important hepatic enzyme of lipoprotein secretion, stearoyl-coenzyme A desaturase-1. CONCLUSIONS: CIH causes atherosclerosis in the presence of diet-induced dyslipidemia.     

Chronic and intermittent hypoxia differentially regulate left ventricular inflammatory and extracellular matrix responses

We evaluated the left ventricle (LV) response to hypoxia by comparing male Sprague Dawley rats exposed for 7 days to normoxia (control; n=18), chronic sustained hypoxia (CSH; n=12) and chronic intermittent hypoxia (CIH; n=12). Out of the 168 inflammatory, extracellular matrix and adhesion molecule genes evaluated, Ltb, Cdh4, Col5a1, Ecm1, MMP-11 and TIMP-2 increased in the LV (range: 87-138%), whereas Tnfrsf1a decreased 27%, indicating an increase in inflammatory status with CSH (all P<0.05). CIH decreased Ltb, Spp1 and Ccl5 levels, indicating reduced inflammatory status. While Laminin β2 gene levels increased 123%, MMP-9 and fibronectin gene levels both decreased 74% in CIH (all P<0.05). Right ventricle/body weight ratios increased in CSH (1.1±0.1?g?g(-1)) compared with control (0.7±0.1?g?g(-1)) and CIH (0.8±0.1?g?g(-1); both P<0.05). Lung to body weight increased in CSH, while LV/body weight ratios were similar among all three groups. With CIH, myocyte cross sectional areas increased 25% and perivascular fibrosis increased 100% (both P<0.05). Gene changes were independent of global changes and were validated by protein levels. MMP-9 protein levels decreased 94% and fibronectin protein levels decreased 42% in CIH (both P<0.05). Consistent with a decreased inflammatory status, HIF-2α and eNOS protein levels were 36% and 44% decreased, respectively, in CIH (both P<0.05). In conclusion, our results indicate that following 7 days of hypoxia, inflammation increases in response to CSH and decreases in response to CIH. This report is the first to demonstrate specific and differential changes seen in the LV during chronic sustained and CIH.     

Chronic hypobaric hypoxia effects on rat colon in vitro sensitivity to acute hypoxia and amiloride

Chronic hypoxia induces many physiological changes, but little is known about its effects on colonic epithelial function. Isolated distal colon mucosa from rats under normobaric conditions and rats submitted to hypobaric hypoxia for either 4 or 10 days was studied in an Ussing chamber. After 4 days of hypoxia, there was only a 15% increase in transepithelial resistivity. However, 10-day hypoxic rats showed higher short circuit current, potential difference, and resistivity. In this group, but not in normal or 4-day hypoxic animals, amiloride dose-dependently depressed short circuit current. The response to acute hypoxia in vitro was unchanged after chronic hypoxia and was not affected by amiloride. Although the amiloride-sensitive increase in short circuit current in 10-day hypoxic rats might resemble mineralocorticoid action, resistivity was increased and serum aldosterone was very low. It is suggested that chronic hypoxia may enhance electrogenic sodium transport by an aldosterone-independent mechanism.     

Cardiovascular response to acute airway obstruction and hypoxia

We wished to evaluate the role of hypoxia in the production of cardiovascular manifestations of acute airway obstruction. We monitored blood pressure, electrocardiogram, and radionuclide ejection fraction in 14 healthy volunteers on exposure to four experimental conditions: expiratory resistive loading while breathing room air (RAL), expiratory resistive loading while hypoxic (HL), hypoxia alone (H), and expiratory resistive loading while voluntarily hyperventilating in a pattern similar to HL trials (VL). Mean respiratory-related oscillation in systolic blood pressure (pulsus paradoxus) increased significantly under each experimental condition compared with those at baseline (2 +/- 2.3 mm Hg): for RAL, 21 +/- 8.4 mm Hg; for HL, 34 +/- 16.3 mm Hg; for H, 10 +/- 5.4 mm Hg; for VL 26 +/- 13.4 mm Hg. Pulsus paradoxus was significantly greater under conditions of moderate hypoxia (saturation, 80%) than of mild hypoxia (saturation, 90%). Electrocardiographic changes were more marked under HL and H conditions than under RAL and VL conditions. HL induced changes in blood pressure and frontal QRS axis that were qualitatively similar to those seen in naturally occurring asthma. Radionuclide ejection fraction showed no dramatic change with any experimental condition. We conclude that hypoxia magnifies the cardiovascular changes induced by acute expiratory resistive loads and may contribute to the degree of pulsus paradoxus seen in severe asthma.     

Prenatal exposure to nicotine impairs protective responses of rat pups to hypoxia in an age-dependent manner.

Experiments were carried out on rat pups to investigate the interaction between prenatal exposure to nicotine and postnatal age on protective responses that promote survival during exposure to hypoxia. From days 6 or 7 of gestation, pregnant rats received either nicotine (approximately 6 mg of nicotine tartrate/kg of body weight per day) or vehicle continuously via a 28-day osmotic minipump. On postnatal days 1--2, 5--6 and 10--11, the pups were exposed either to a single period of hypoxia produced by breathing an anoxic gas mixture (97% N(2) and 3% CO(2)) and their time to last gasp determined, or they were exposed repeatedly to hypoxia and their ability to autoresuscitate from primary apnea determined. Prenatal exposure to nicotine decreased the time to last gasp, but only in the 1--2-day-old animals. The total number of gasps was, however, increased in this age group due to the effect of nicotine on the gasping pattern. Furthermore, prenatal exposure to nicotine decreased the number of successful autoresuscitations and influenced the cardiorespiratory events preceding death in the 1--2- and 5--6-day-old pups but not in the 10--11-day-old pups. Thus, our experiments show that prenatal exposure to nicotine impairs protective responses of rat pups that may sustain life during exposure to hypoxia in an age-dependent manner.     

Chronic intermittent hypoxia increases haematocrit and causes right ventricular hypertrophy in the rat.

Chronic continuous hypoxia increases haematocrit and causes right ventricular hypertrophy and pulmonary hypertension. In obstructive sleep apnoea, the exposure to hypoxia is intermittent rather than continuous but the effects of chronic intermittent hypoxia on haematocrit and right ventricular mass are unclear. Wistar rats were exposed to alternating periods of hypoxia and normoxia twice per min for 8 h per day for 5 weeks in order to mimic the intermittent hypoxia of obstructive sleep apnoea in humans. Haematocrit was significantly raised at day 7, 14, 21, 28 and 35 of the treatment period. At the end of the treatment, there was a significant increase in right ventricular mass. Therefore, chronic intermittent hypoxia increases haematocrit and right heart mass. These results suggest that the raised haematocrit and pulmonary arterial pressure observed in some cases of obstructive sleep apnoea in humans may be caused by intermittent nocturnal hypoxaemia.     

Effects of age and gender on rat upper airway muscle contractile properties

Upper airway muscles regulate upper airway patency. Obstructive sleep apnea is caused by upper airway collapse, and its incidence increases with age and is higher in men than women. The reasons for this are unknown, as little is known about the effects of age and gender on upper airway muscle. Isometric contractile properties were determined using strips of geniohyoid and sternohyoid muscles from young and old, male and female rats in physiological saline solution at 30 degrees C. There were no differences between the male and female rats in any of the contractile properties of either muscle, and this was true for both young and old animals. Aging had no effect on sternohyoid contractile properties, but geniohyoid force was greater in old than in young rats.     

Exposure to intermittent hypoxia inhibits allergic airway inflammation in a murine model of asthma

Sleep and Breathing - Obesity increases the severity of asthma, and patients with severe asthma are often complicated with obstructive sleep apnea syndrome (OSAS), a concomitant disease of obesity....     

Metabolic responses to intermittent hepatic dearterialization in the rat

Hepatic dearterialization is a palliative treatment for irresectable liver tumours. In the current study, the metabolic consequences of hepatic dearterialization were examined in the rat. Liver glycogen content was reduced to an average of 84% following 60 min dearterialization and was further reduced to an average of 16% following 60 min reperfusion. Plasma concentration of beta-hydroxybutyric acid was elevated by an average of 65% following 60 min hepatic dearterialization. In contrast, hepatic dearterialization did not alter cholesterol and triglyceride plasma levels. In addition, the hepatic activity of hepatic lipase was reduced by 29% after 60 min of hepatic dearterialization, a reduction which remained after 60 min of reperfusion. Clearance of intravenously administered antipyrine, which reflects the activity of liver microsomal enzymes, was reduced by 37% after 60 min of hepatic dearterialization. In conclusion hepatic dearterialization is accompanied by marked activity in the processes related to carbohydrate, lipid and xenobiotic metabolism. These effects should be taken into account when treating patients with hepatic dearterialization.     

Contractile responses of isolated rat mesenteric arteries to acute episodes of severe hypoxia and subsequent reoxygenation

This study further investigates the mechanisms responsible for the effects of acute and severe hypoxia, and subsequent reoxygenation, on the contractility of isolated rat mesenteric arteries. In noradrenaline (NA)-contracted arteries, hypoxia caused a relaxation to near baseline levels. Reoxygenation resulted in an immediate transient contraction before tension returned more slowly to prehypoxia levels. Similar responses to hypoxia were observed in tissues precontracted by addition of KCl (60 mM) or U46619 (10 microM); however, the transient contraction upon reoxygenation was absent (KCl) or reduced (U46619). Responses to hypoxia were independent of changes in intracellular calcium ([Ca2+]i), while those to reoxygenation were accompanied by corresponding changes in [Ca2+]i and were completely abolished by ryanodine. In NA-contracted tissues, all responses were unaffected by endothelial removal or by inhibitors of nitric oxide synthase and cyclooxygenase. The K+ channel blockers triethylamine (TEA), glibenclamide, and 4-aminopyridine (4-AP) had no effect on the responses to hypoxia. The transient contractile response to reoxygenation was, however, significantly reduced in the presence of 4-AP. The response to reoxygenation, but not that to hypoxia, was inhibited by the antioxidant dithiothreitol (DTT) and the NAD(P)H-oxidase inhibitor diphenyliodonium (DPI). These data suggest that hypoxic vasodilation occurs independently of reductions in [Ca2+]i. Alternatively, transient contractions on reoxygenation are dependent upon the generation of reactive oxygen species and the release of stored Ca2+.     

Electric stimulation of the upper airway muscle

In various studies, it has been postulated that pharyngeal collapse occurring during sleep in obstructive sleep apnea may be alleviated by stimulating the genioglossus muscle. Basic experiments have demonstrated that neuromuscular stimulation applied intraorally via electrodes or by direct neural stimulation of the hypoglossal nerve might improve upper airway and respiratory function. An increase of maximal inspiratory airflow, an improvement of upper airway collapsibility and a decrease in respiratory events during sleep were observed. An impairment of sleep quality during electric stimulation has been excluded simultaneously. Considering clinical aspects, anatomical properties and long-term experience in electric stimulation it might be possible to develop full implantable devices as an alternative treatment for patients with obstructive sleep apnea.     

Changes in inspiratory muscle electrical activity and upper airway resistance during periodic breathing induced by hypoxia during sleep

We hypothesized that: the balance of electrical activities between the upper airway and chest wall inspiratory muscles affects upper airway inspiratory caliber, and at low levels of central respiratory neural efferent activity, an imbalance between the electrical activities of these 2 inspiratory muscle groups exists that results in a decreased upper airway caliber. These hypotheses were tested during periodic breathing induced by mild hypoxemia in NREM sleep in 9 healthy male subjects. In 6 subjects during periodic breathing as central respiratory neural activity decreased, the tonic and phasic EMG activity of the upper airway inspiratory muscles decreased at a rate greater than that of the chest wall EMG activity. When the ratio of upper airway to chest wall EMG activity decreased below a critical level, which was reproducible across subjects, upper airway inspiratory resistance increased hyperbolically. Resistance at peak inspiratory flow increased from 4.10 +/- 0.97 (mean +/- SEM) to 48.70 +/- 21.00 cmH2O/L/s as tidal volume decreased from 0.79 +/- 0.12 to 0.20 +/- 0.02 L during periodic breathing in these subjects. In the 3 remaining subjects, the ratio of the upper airway to chest wall EMG activity did not decrease below the critical level as the activity of both muscle groups decreased during periodic breathing, and upper airway resistance did not increase. We conclude that within the confines of this study the nonlinear activation of upper airway and chest wall inspiratory muscles contributed to fluctuations in upper airway resistance observed during periodic breathing in sleep.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic intermittent hypoxia exposure induces kidney injury in growing rats

Sleep and Breathing - The objectives of this paper are to examine the effect of chronic intermittent hypoxia (CIH) on the morphological changes in the kidney of growing rats and to explore the...