Short-term intermittent hypoxia enhances sympathetic responses to continuous hypoxia in 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; O(2) 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 O(2) (Fi(O(2))) 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 (Fi(O(2)) 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.     

Intermittent hypoxia: cause of or therapy for systemic hypertension?

During acute episodes of hypoxia, chemoreceptor-mediated sympathetic activity increases heart rate, cardiac output, peripheral resistance and systemic arterial pressure. However, different intermittent hypoxia paradigms produce remarkably divergent effects on systemic arterial pressure in the post-hypoxic steady state. The hypertensive effects of obstructive sleep apnea (OSA) vs. the depressor effects of therapeutic hypoxia exemplify this divergence. OSA, a condition afflicting 15-25% of American men and 5-10% of women, has been implicated in the pathogenesis of systemic hypertension and is a major risk factor for heart disease and stroke. OSA imposes a series of brief, intense episodes of hypoxia and hypercapnia, leading to persistent, maladaptive chemoreflex-mediated activation of the sympathetic nervous system which culminates in hypertension. Conversely, extensive evidence in animals and humans has shown controlled intermittent hypoxia conditioning programs to be safe, efficacious modalities for prevention and treatment of hypertension. This article reviews the pertinent literature in an attempt to reconcile the divergent effects of intermittent hypoxia therapy and obstructive sleep apnea on hypertension. Special emphasis is placed on research conducted in the nations of the former Soviet Union, where intermittent hypoxia conditioning programs are being applied therapeutically to treat hypertension in patients. Also reviewed is evidence regarding mechanisms of the pro- and anti-hypertensive effects of intermittent hypoxia.     

Carotid body function and ventilatory responses in intermittent hypoxia. Evidence for anomalous brainstem integration of arterial chemoreceptor input

Obstructive sleep apnea is a frequent medical condition consisting in repetitive sleep-related episodes of upper airways obstruction and concurrent events of arterial blood hypoxia. There is a frequent association of cardiovascular diseases and other pathologies to this condition conforming the obstructive sleep apnea syndrome (OSAS). Laboratory models of OSAS consist in animals exposed to repetitive episodes of intermittent hypoxia (IH) which also develop cardiovascular pathologies, mostly hypertension. The overall OSAS pathophysiology appears to be linked to the repetitive hypoxia, which would cause a sensitization of carotid body (CB) chemoreflex and chemoreflex-driven hyperreactivity of the sympathetic nervous system. However, this proposal is uncertain because hyperventilation, reflecting the CB sensitization, and increased plasma CA levels, reflecting sympathetic hyperreactivity, are not constant findings in patients with OSAS and IH animals. Aiming to solve these uncertainties we have studied the entire CB chemoreflex arch in a rat model of IH, including activity of chemoreceptor cells and CB generated afferent activity to brainstem. The efferent activity was measured as ventilation in normoxia, hypoxia, and hypercapnia. Norepinephrine turnover in renal artery sympathetic endings was also assessed. Findings indicate a sensitization of the CB function to hypoxia evidenced by exaggerated chemoreceptor cell and CB afferent activity. Yet, IH rats exhibited marked hypoventilation in all studied conditions and increased turnover of norepinephrine in sympathetic endings. We conclude that IH produces a bias in the integration of the input arising from the CB with a diminished drive of ventilation and an exaggerated activation of brainstem sympathetic neurons.     

Ventilatory, hemodynamic, sympathetic nervous system, and vascular reactivity changes after recurrent nocturnal sustained hypoxia in humans

Recurrent and intermittent nocturnal hypoxia is characteristic of several diseases including chronic obstructive pulmonary disease, congestive heart failure, obesity-hypoventilation syndrome, and obstructive sleep apnea. The contribution of hypoxia to cardiovascular morbidity and mortality in these disease states is unclear, however. To investigate the impact of recurrent nocturnal hypoxia on hemodynamics, sympathetic activity, and vascular tone we evaluated 10 normal volunteers before and after 14 nights of nocturnal sustained hypoxia (mean oxygen saturation 84.2%, 9 h/night). Over the exposure, subjects exhibited ventilatory acclimatization to hypoxia as evidenced by an increase in resting ventilation (arterial Pco(2) 41.8 +/- 1.5 vs. 37.5 +/- 1.3 mmHg, mean +/- SD; P < 0.05) and in the isocapnic hypoxic ventilatory response (slope 0.49 +/- 0.1 vs. 1.32 +/- 0.2 l/min per 1% fall in saturation; P < 0.05). Subjects exhibited a significant increase in mean arterial pressure (86.7 +/- 6.1 vs. 90.5 +/- 7.6 mmHg; P < 0.001), muscle sympathetic nerve activity (20.8 +/- 2.8 vs. 28.2 +/- 3.3 bursts/min; P < 0.01), and forearm vascular resistance (39.6 +/- 3.5 vs. 47.5 +/- 4.8 mmHg.ml(-1).100 g tissue.min; P < 0.05). Forearm blood flow during acute isocapnic hypoxia was increased after exposure but during selective brachial intra-arterial vascular infusion of the alpha-blocker phentolamine it was unchanged after exposure. Finally, there was a decrease in reactive hyperemia to 15 min of forearm ischemia after the hypoxic exposure. Recurrent nocturnal hypoxia thus increases sympathetic activity and alters peripheral vascular tone. These changes may contribute to the increased cardiovascular and cerebrovascular risk associated with clinical diseases that are associated with chronic recurrent hypoxia.     

Cardiovascular and ventilatory acclimatization induced by chronic intermittent hypoxia: a role for the carotid body in the pathophysiology of sleep apnea

Patients with obstructive sleep apnea (OSA) show augmented ventilatory, sympathetic and cardiovascular responses to hypoxia. The facilitatory effect of chronic intermittent hypoxia (CIH) on the hypoxic ventilatory response has been attributed to a potentiation of the carotid body (CB) chemosensory response to hypoxia. However, it is a matter of debate whether the effects induced by CIH on ventilatory responses to hypoxia are due to an enhanced CB activity. Recently, we studied the effects of short cyclic hypoxic episodes on cat cardiorespiratory reflexes, heart rate variability, and CB chemosensory activity. Cats were exposed to cyclic hypoxic episodes repeated during 8 hours for 4 days. Our results showed that CIH selectively enhanced ventilatory and carotid chemosensory responses to acute hypoxia. Exposure to CIH did not increase basal arterial pressure, heart rate, or their changes induced by acute hypoxia. However, the spectral analysis of heart rate variability of CIH cats showed a marked increase of the low/high frequency ratio and an increased variability in the low frequency band of heart rate variability, similar to what is observed in OSA patients. Thus, it is likely that the enhanced CB reactivity to hypoxia may contribute to the augmented ventilatory response to hypoxia.     

Invited review: Physiological and pathophysiological responses to intermittent hypoxia.

This mini-review summarizes the physiological adaptations to and pathophysiological consequences of intermittent hypoxia with special emphasis given to the pathophysiology associated with obstructive sleep apnea. Intermittent hypoxia is an effective stimulus for evoking the respiratory, cardiovascular, and metabolic adaptations normally associated with continuous chronic hypoxia. These adaptations are thought by some to be beneficial in that they may provide protection against disease as well as improve exercise performance in athletes. The long-term consequences of chronic intermittent hypoxia may have detrimental effects, including hypertension, cerebral and coronary vascular problems, developmental and neurocognitive deficits, and neurodegeneration due to the cumulative effects of persistent bouts of hypoxia. Emphasis is placed on reviewing the available data on intermittent hypoxia, making extensions from applicable information from acute and chronic hypoxia studies, and pointing out major gaps in information linking the genomic and cellular responses to intermittent hypoxia with physiological or pathophysiological responses.     

Blood pressure response to chronic episodic hypoxia: the renin-angiotensin system.

By using an inspired oxygen fraction that produces oxyhemoglobin desaturation equivalent to that seen in human sleep apnea, we have demonstrated that 35 days of recurrent episodic hypoxia (every 30 s for 7 h/day) results in an 8-13 mmHg persistent increase in diurnal systemic mean arterial blood pressure (MAP) in rats. Blockade of angiotensin II receptors (AT(1a)) eliminates this response. Separate groups of male Sprague-Dawley rats were fed high-salt (8%), ad libitum-salt, or low-salt (0.1%) diets for 7 wk: 2 wk of wash-in for baseline blood pressure measurement and 5 wk of experimental conditions. Rats in each salt group were subjected to episodic hypoxia whereas controls remained unhandled under normoxic conditions. MAP remained at basal levels in all nonepisodic hypoxia controls as well as high-salt-diet episodic hypoxia-exposed rats. Ad lib and low-salt episodic hypoxia rats showed an increase in MAP from 106 and 104 mmHg at baseline to 112 and 113 mmHg, respectively (P < 0.05). Whole kidney renin mRNA was suppressed in high-salt controls and episodic hypoxia rats, whereas kidney AT(1a) mRNA showed opposite changes. Suppression of the renin-angiotensin system with a high-salt diet blocks the increase in MAP in episodic hypoxia-challenged rats, in part by suppressing local tissue renin levels. Upregulation of the tissue angiotensin II system appears to be necessary for the chronic blood pressure changes that occur from episodic hypoxia.     

Selected Contribution: Pulmonary hypertension in mice following intermittent hypoxia.

Sleep apnea (intermittent periods of hypoxia with or without hypercapnia) is associated with systemic hypertension and increased mortality from cardiovascular disease, but the relationship to pulmonary hypertension is uncertain. Previous studies on intermittent hypoxia (IH) in rats that demonstrated pulmonary hypertension utilized relatively long periods of hypoxia. Recent studies that utilized brief periods of hypoxia have conflicting reports of right ventricular (RV) hypertrophy. In addition, many studies have not measured pulmonary hemodynamics to asses the severity of pulmonary hypertension in vivo. Given the increasing availability of genetically engineered mice and the need to establish a rodent model of IH-induced pulmonary hypertension, we studied the effect of IH (2-min cycles of 10% and 21% O2, 8 h/day, 4 wk) on wild-type mice, correlating in vivo measurements of pulmonary hypertension with RV mass and pulmonary vascular remodeling. RV systolic pressure was increased after IH (36 +/- 0.9 mmHg) compared with normoxia (29.5 +/- 0.6) but was lower than continuous hypoxia (44.2 +/- 3.4). RV mass [RV-to-(left ventricle plus septum) ratio] correlated with pressure measurements (IH = 0.27 +/- 0.02, normoxia = 0.22 +/- 0.01, and continuous hypoxia = 0.34 +/- 0.01). Hematocrits were also elevated after IH and continuous hypoxia (56 +/- 1.6 and 54 +/- 1.1 vs. 44.3 +/- 0.5%). Evidence of neomuscularization of the distal pulmonary circulation was found after IH and continuous hypoxia. We conclude that mice develop pulmonary hypertension following IH, representing a possible animal model of pulmonary hypertension in response to the repetitive hypoxia-reoxygenation of sleep apnea.     

Endothelin-1-Mediated Mechanisms in the Carotid Body Modulates Cardiovascular Responses in Rats Exposed to Chronic Intermittent Hypoxia

Chronic intermittent hypoxia (CIH), the main feature of obstructive sleep apnea (OSA), is associated with hypertension. The increased of carotid body (CB) sensitivity due to enhanced sympathetic efferent may be mainly responsible for the elevation of blood pressure. Accordingly, we studied this effect of Endothelin-1 (ET-1)-induced CB chemosensory response to CIH, as a vasoactive peptide expressed in CB. The purpose of this study was to investigate the mean arterial blood pressure (MAP) and renal sympathetic nerve activity (RSNA) responses in CIH group by injecting ET-1 to directly stimulate CB chemoreceptor. Furthermore, whether ET receptor-mediated PKC and p³⁸MAPK signaling pathway was involved in CIH-induced CB activation was also studied. Male Sprague–Dawley rats were exposed to CIH (8 h/day for 3 weeks) and the MAP and RSNA were recorded in CIH rats and Sham rats. Our results demonstrated that ET-1-induced MAP and RSNA increase were mainly mediated by ET_A receptor activation in CB chemosensory after CIH exposure. Moreover, P³⁸MAPK and PKC signaling pathway might be involved in ET-1-induced increase of MAP and RSNA in CIH group, which provided a potential therapeutic target of OSA.

     

阻塞性睡眠呼吸暂停综合征与高血压临床关系分析

目的:研究阻塞性睡眠呼吸暂停综合征与高血压的临床关系及相关机制。方法:将258例鼾症患者分为三组:单纯鼾症对照组(N组)、单纯OSAHS组(O组)、OSAHS合并高血压组(O+H组)。对三组患者进行临床基础资料收集,ESS问卷调查及EP评分,多导睡眠监测及血压测定。结果:三组鼾症患者之间年龄、性别、吸烟、饮酒差异无统计学意义(P>0.05),OSAHS组及OSAHS+HT组体重指数及颈围明显高于单纯鼾症组,差异有统计学意义(P<0.05);与单纯鼾症组比较,OSAHS组及OSAHS+HT组的EP评分、AHI、LaSO2(%)、MSaO2、Ts90%差异明显有统计学意义(P<0.05);与对照组相比OSAHS组及OSAHS+HT组睡眠前后收缩压和舒张压升高,差异有统计学意义(P<0.05)。结论:阻塞性睡眠呼吸暂停综合征与高血压关系密切,慢性间歇缺氧是引起高血压的核心机制。     

Invited review: Neural network plasticity in respiratory control.

Respiratory network plasticity is a modification in respiratory control that persists longer than the stimuli that evoke it or that changes the behavior produced by the network. Different durations and patterns of hypoxia can induce different types of respiratory memories. Lateral pontine neurons are required for decreases in respiratory frequency that follow brief hypoxia. Changes in synchrony and firing rates of ventrolateral and midline medullary neurons may contribute to the long-term facilitation of breathing after brief intermittent hypoxia. Long-term changes in central respiratory motor control may occur after spinal cord injury, and the brain stem network implicated in the production of the respiratory rhythm could be reconfigured to produce the cough motor pattern. Preliminary analysis suggests that elements of brain stem respiratory neural networks respond differently to hypoxia and hypercapnia and interact with areas involved in cardiovascular control. Plasticity or alterations in these networks may contribute to the chronic upregulation of sympathetic nerve activity and hypertension in sleep apnea syndrome and may also be involved in sudden infant death syndrome.     

Enhanced sympathetic outflow and decreased baroreflex sensitivity are associated with intermittent hypoxia-induced systemic hypertension in conscious rats.

Long-term exposure to intermittent hypoxia (IH), such as that occurring in association with sleep apnea, may result in systemic hypertension; however, the time course changes in arterial pressure, autonomic functions, and baroreflex sensitivity are still unclear. We investigated the changes in cardiovascular neural regulations during the development of chronic IH-induced hypertension in rats. Sprague-Dawley rats were exposed to repetitive 1.25-min cycles (30 s of N2+45 s of 21% O2) of IH or room air (RA) for 6 h/day during light phase (10 AM-4 PM) for 30 days. Arterial pressure was measured daily using the telemetry system during RA breathing. The mean arterial pressure (MAP) and interpulse interval (PPI) signals were then used to assess the autonomic functions and spontaneous baroreflex sensitivity by auto- and cross-spectral analysis, respectively. Stable MAP, low-frequency power of MAP (BLF), and low-frequency power (LF)-to-high frequency power (HF) ratio of PPI (LF/HF) were significantly higher in IH-exposed rats, compared with those of RA-exposed rats. Elevation of the MAP, BLF, LF/HF, and minute ventilation started 5 days after IH exposure and lasted until the end of the 30-day observation period. Additionally, IH-exposed rats had significant lower slope of MAP-PPI linear regression (under a successively descending and ascending) and magnitude of MAP-PPI transfer function (at frequency ranges of 0.06-0.6 Hz or 0.6-2.4 Hz) after IH exposure for 17 days. However, RA-exposed rats did not exhibit these changes. The results of this study indicate that chronic IH-induced hypertension is associated with a facilitation of cardiovascular sympathetic outflow and inhibition of baroreflex sensitivity in conscious rats.     

Neonatal intermittent hypoxia and hypertension

Obstructive apnea during sleep is accompanied by intermittent hypoxia (IH) leading to hypertension and other cardiovascular disturbances. A comparative evaluation of long-term effects of the neonatal IH on the cardiovascular functions was performed in normotensive Sprague-Dawley and spontaneously hypertensive rats (SHR). The newborn rats were placed for 30 days to conditions of IH (8% and 21% O₂, alternating every 90 s for 12 h/day). Control groups of rats were constantly kept in normoxia. By 6 months, in the spontaneously hypertensive rats exposed to IH at the period of wakefulness there was a statistically significant increase (as compared with control) of the systolic (185.8 ± 1.7 and 169.9 ± 1.4 mm Hg, correspondingly, p < 0.010 and the diastolic pressure (96.2 ± 4.9 and 86.0 ± 2.6 mm Hg, correspondingly, p < 0.01). During sleep, the systolic and diastolic pressure in these rats was higher than in control animals by 10 mm Hg (p < 0.01) and 12 mm Hg (p < 0.01), its decrease during sleep being absent. In SHR submitted to IH there was an increase in the power ratio of the heart rate variability from 0.9 ± 0.15 to 1.5 ± 0.17, which indicates a shift of the sympathico-parasympathetic balance in this group towards predominance of the sympathetic component. In the Sprague-Dawley rats exposed to neonatal hypoxia, the above-indicated changes were not prominent. These peculiarities of the hypertensive rats allow establishing connection of the genetic factor with the sympathetic mechanism providing long-term consequences of the neonatal IH for the cardiovascular control in the SHR.     

Quintessential Risk Factors: Their Role in Promoting Cognitive Dysfunction and Alzheimer’s Disease

Alzheimer??s disease (AD) is a progressive neurodegenerative disorder. The human brain is extremely sensitive to hypoxia, ischemia, and glucose depletion. Impaired delivery of oxygen in obstructive sleep apnea (OSA) alters neuronal homeostasis, induces pathology, and triggers neuronal degeneration/death. This article systematically delineates the steps in the complex cascade leading to AD, focusing on pathology caused by chronic intermittent hypoxia, hypertension, brain hypoperfusion, glucose dysmetabolism, and endothelial dysfunction. Hypoxia/hypoxemia underpins several pathological processes including sympathetic activation, chemoreflex activity, neuroinflammation, oxidative stress, and a host of perturbations leading to neurodegeneration. The arterial blood flow reduction in OSA is profound, being about 76?% in obstructive hypopneas and 80?% in obstructive apneas; this leads to cerebral ischemia promoting neuronal apoptosis in neocortex and brainstem. OSA pathology also includes gray matter loss in the frontal, parietal, temporal, and occipital cortices, the thalamus, hippocampus, and key brainstem nuclei including the nucleus tractus solitarius. (18)F-FDG PET studies on OSA and AD patients, and animal models of AD, have shown reduced cerebral glucose metabolism in the above mentioned brain regions. Owing to the pathological impact of hypoxia, hypertension, hypoperfusion and impaired glucose metabolism, the adverse cardiovascular, neurocirculatory and metabolic consequences upregulate amyloid beta generation and tau phosphorylation, and lead to memory/cognitive impairment??culminating in AD. The framework encompassing these factors provides a pragmatic neuropathological approach to explain onset of Alzheimer??s dementia. The basic tenets of the current paradigm should influence the design of therapeutic strategies to ameliorate AD.     

Obstructive sleep apnea and chronic intermittent hypoxia: a review

Hypoxia is an important topic both physiologically and clinically. Traditionally, physiology research has been focusing on the effect of acute and chronic sustained hypoxia and human adaptive response to high altitude. In the past 20 years, genetic studies by many have expanded our understanding of hypoxia to the molecular level. However, in contrast to our extensive knowledge about acute and chronic sustained hypoxia, we know relatively little about the effect of chronic intermittent hypoxia (CIH). In recent years, CIH has attracted more research attention because of the increasing prevalence of obesity and obstructive sleep apnea (OSA) in the western countries. Clinically, CIH is commonly seen in patients with sleep-disordered breathing including OSA, Cheyne-Stokes respiration and nocturnal hypoventilation. It was estimated that for OSA of at least mild severity prevalence estimates range from 3 to 28% in the general population. OSA is characterized by recurrent upper airway collapse during sleep leading to intermittent nocturnal hypoxia and sleep fragmentation. OSA is associated with significant mortality and morbidity including neurocognitive dysfunction, hypertension, many cardiovascular disorders and metabolic disorders such as diabetes and metabolic syndrome. The intermittent hypoxia in OSA closely mimics what is seen in the ischemia-reperfusion injury. Experimentally, there is no universally accepted definition for CIH. Laboratory protocols vary greatly in duration of hypoxia exposure, numbers of hypoxia episodes per day and the total number of days of exposure. Despite the lack of a uniform definition, recent data suggest that CIH may lead to multiple long-term pathophysiologic consequences similar to what we see in patients with OSA. Recent evidences also demonstrate that there are remarkable differences in the response of the physiologic systems to sustained hypoxia and intermittent hypoxia. This review is aimed to briefly discuss the clinical significance of sleep-disordered breathing and our current understanding of CIH.     

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

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.     

Reactive oxygen species contribute to sleep apnea-induced hypertension in rats

In clinical studies, sleep apnea is associated with hypertension, oxidative stress, and increased circulating endothelin-1 (ET-1). We previously developed a model of sleep apnea by exposing rats to eucapnic intermittent hypoxia (IH-C) during sleep, which increases both blood pressure and plasma levels of ET-1. Because similar protocols in mice increase tissue and plasma markers of oxidative stress, we hypothesized that IH-C generation of reactive oxygen species (ROS) contributes to the development of ET-1-dependent hypertension in IH-C rats. To test this, male Sprague-Dawley rats were instrumented with indwelling blood pressure telemeters and drank either plain water or water containing the superoxide dismutase mimetic, Tempol (4-hydroxy-2,2,6,6-tetramethyl-piperidine-1-oxyl, 1 mM). Mean arterial pressure (MAP) and heart rate (HR) were recorded for 3 control days and 14 treatment days with rats exposed 7 h/day to IH-C or air/air cycling (Sham). On day 14, MAP in IH-C rats treated with Tempol (107 +/- 2.29 mmHg) was significantly lower than in untreated IH-C rats (118 +/- 9 mmHg, P < 0.05). Tempol did not affect blood pressure in sham-operated rats (Tempol = 101 +/- 3, water = 101 +/- 2 mmHg). Immunoreactive ET-1 was greater in plasma from IH-C rats compared with plasma from sham-operated rats but was not different from Sham in Tempol-treated IH-C rats. Small mesenteric arteries from IH-C rats but not Tempol-treated IH-C rats had increased superoxide levels as measured by ferric cytochrome c reduction, lucigenin signaling, and dihydroethidium fluorescence. The data show that IH-C increases ET-1 production and vascular ROS levels and that scavenging superoxide prevents both. Thus oxidative stress appears to contribute to increases in ET-1 production and elevated arterial pressure in this rat model of sleep apnea-induced hypertension.     

慢性间歇性缺氧对大鼠肺组织凋亡相关基因Bcl-2、Bax表达的影响

目的探讨凋亡(apoptosis)相关基因Bcl-2、Bax在慢性间歇性缺氧(chronic intermittent hypoxia,CIH)大鼠肺组织中的表达,明确其与阻塞性睡眠呼吸暂停低通气综合征(obstructive sleep apnea hypopnea syndrome,OSAHS)肺部病变的关系.方法取健康雄性Sprague-Dawley(S-D)大鼠20只,随机分为正常对照组(A组)和CIH组(B组),每组10只,根据实验要求,将B组大鼠暴露于CIH的环境中,8h/d(上午9时至下午5时),共5w,以模拟OSAHS患者CIH的特征.A组大鼠常规饲养,不予以任何处理.采用免疫组织化学方法(SP法)检测大鼠肺组织中Bcl-2、Bax蛋白的表达.结果大鼠肺组织中阳性细胞表达部位主要集中于支气管上皮细胞和肺泡上皮细胞.正常大鼠Bcl-2、Bax蛋白均有基础低表达,经CIH处理后可见大鼠支气管上皮细胞和肺泡上皮细胞Bcl-2、Bax蛋白表达的上调和Bax/bcl-2比值的升高.结论 CIH可导致大鼠肺组织细胞凋亡的增加,凋亡参与了CIH大鼠肺部病变的病理生理过程;Bcl-2和Bax这一对凋亡抑制和促进基因参与了CIH过程中大鼠肺组织细胞凋亡的调控.     

Central chemoreflex sensitivity and sympathetic neural outflow in elite breath-hold divers.

Repeated hypoxemia in obstructive sleep apnea patients increases sympathetic activity, thereby promoting arterial hypertension. Elite breath-holding divers are exposed to similar apneic episodes and hypoxemia. We hypothesized that trained divers would have increased resting sympathetic activity and blood pressure, as well as an excessive sympathetic nervous system response to hypercapnia. We recruited 11 experienced divers and 9 control subjects. During the diving season preceding the study, divers participated in 7.3 +/- 1.2 diving fish-catching competitions and 76.4 +/- 14.6 apnea training sessions with the last apnea 3-5 days before testing. We monitored beat-by-beat blood pressure, heart rate, femoral artery blood flow, respiration, end-tidal CO(2), and muscle sympathetic nerve activity (MSNA). After a baseline period, subjects began to rebreathe a hyperoxic gas mixture to raise end-tidal CO(2) to 60 Torr. Baseline MSNA frequency was 31 +/- 11 bursts/min in divers and 33 +/- 13 bursts/min in control subjects. Total MSNA activity was 1.8 +/- 1.5 AU/min in divers and 1.8 +/- 1.3 AU/min in control subjects. Arterial oxygen saturation did not change during rebreathing, whereas end-tidal CO(2) increased continuously. The slope of the hypercapnic ventilatory and MSNA response was similar in both groups. We conclude that repeated bouts of hypoxemia in elite, healthy breath-holding divers do not lead to sustained sympathetic activation or arterial hypertension. Repeated episodes of hypoxemia may not be sufficient to drive an increase in resting sympathetic activity in the absence of additional comorbidities.