Exercise training improves peripheral chemoreflex function in heart failure rabbits.

An enhancement of peripheral chemoreflex sensitivity contributes to sympathetic hyperactivity in chronic heart failure (CHF) rabbits. The enhanced chemoreflex function in CHF involves augmented carotid body (CB) chemoreceptor activity via upregulation of the angiotensin II (ANG II) type 1 (AT(1))-receptor pathway and downregulation of the neuronal nitric oxide synthase (nNOS)-nitric oxide (NO) pathway in the CB. Here we investigated whether exercise training (EXT) normalizes the enhanced peripheral chemoreflex function in CHF rabbits and possible mechanisms mediating this effect. EXT partially, but not fully, normalized the exaggerated baseline renal sympathetic nerve activity (RSNA) and the response of RSNA to hypoxia in CHF rabbits. EXT also decreased the baseline CB nerve single-fiber discharge (4.9 +/- 0.4 vs. 7.7 +/- 0.4 imp/s at Po(2) = 103 +/- 2.3 Torr) and the response to hypoxia (20.6 +/- 1.1 vs. 36.3 +/- 1.3 imp/s at Po(2) = 41 +/- 2.2 Torr) from CB chemoreceptors in CHF rabbits, which could be reversed by treatment of the CB with ANG II or a nNOS inhibitor. Our results also showed that NO concentration and protein expression of nNOS were increased in the CBs from EXT + CHF rabbits, compared with that in CHF rabbits. On the other hand, elevated ANG II concentration and AT(1)-receptor overexpression of the CBs in CHF state were blunted by EXT. These results indicate that EXT normalizes the CB chemoreflex in CHF by preventing an increase in afferent CB chemoreceptor activity. EXT reverses the alterations in the nNOS-NO and ANG II-AT(1)-receptor pathways in the CB responsible for chemoreceptor sensitization in CHF.     

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.     

Influence of ventilation and hypocapnia on sympathetic nerve responses to hypoxia in normal humans

The sympathetic response to hypoxia depends on the interaction between chemoreceptor stimulation (CRS) and the associated hyperventilation. We studied this interaction by measuring sympathetic nerve activity (SNA) to muscle in 13 normal subjects, while breathing room air, 14% O2, 10% O2, and 10% O2 with added CO2 to maintain isocapnia. Minute ventilation (VE) and blood pressure (BP) increased significantly more during isocapnic hypoxia (IHO) than hypocapnic hypoxia (HHO). In contrast, SNA increased more during HHO [40 +/- 10% (SE)] than during IHO (25 +/- 19%, P less than 0.05). To determine the reason for the lesser increase in SNA with IHO, 11 subjects underwent voluntary apnea during HHO and IHO. Apnea potentiated the SNA responses to IHO more than to HHO. SNA responses to IHO were 17 +/- 7% during breathing and 173 +/- 47% during apnea whereas SNA responses to HHO were 35 +/- 8% during breathing and 126 +/- 28% during apnea. During ventilation, the sympathoexcitation of IHO (compared with HHO) is suppressed, possibly for two reasons: 1) because of the inhibitory influence of activation of pulmonary afferents as a result of a greater increase in VE, and 2) because of the inhibitory influence of baroreceptor activation due to a greater rise in BP. Thus in humans, the ventilatory response to chemoreceptor stimulation predominates and restrains the sympathetic response. The SNA response to chemoreceptor stimulation represents the net effect of the excitatory influence of the chemoreflex and the inhibitory influence of pulmonary afferents and baroreceptor afferents.     

Blunted muscle vasodilatation during chemoreceptor stimulation in patients with heart failure

Chemoreflex control of sympathetic nerve activity is exaggerated in heart failure (HF) patients. However, the vascular implications of the augmented sympathetic activity during chemoreceptor activation in patients with HF are unknown. We tested the hypothesis that the muscle blood flow responses during peripheral and central chemoreflex stimulation would be blunted in patients with HF. Sixteen patients with HF (49 +/- 3 years old, Functional Class II-III, New York Heart Association) and 11 age-paired normal controls were studied. The peripheral chemoreflex control was evaluated by inhalation of 10% O(2) and 90% N(2) for 3 min. The central chemoreflex control was evaluated by inhalation of 7% CO(2) and 93% O(2) for 3 min. Muscle sympathetic nerve activity (MSNA) was directly evaluated by microneurography. Forearm blood flow was evaluated by venous occlusion plethysmography. Baseline MSNA were significantly greater in HF patients (33 +/- 3 vs. 20 +/- 2 bursts/min, P = 0.001). Forearm vascular conductance (FVC) was not different between the groups. During hypoxia, the increase in MSNA was significantly greater in HF patients than in normal controls (9.0 +/- 1.6 vs. 0.8 +/- 2.0 bursts/min, P = 0.001). The increase in FVC was significantly lower in HF patients (0.00 +/- 0.10 vs. 0.76 +/- 0.25 units, P = 0.001). During hypercapnia, MSNA responses were significantly greater in HF patients than in normal controls (13.9 +/- 3.2 vs. 2.1 +/- 1.9 bursts/min, P = 0.001). FVC responses were significantly lower in HF patients (-0.29 +/- 0.10 vs. 0.37 +/- 0.18 units, P = 0.001). In conclusion, muscle vasodilatation during peripheral and central chemoreceptor stimulation is blunted in HF patients. This vascular response seems to be explained, at least in part, by the exaggerated MSNA responses during hypoxia and hypercapnia.     

Cardiac sympathetic afferent stimulation augments the arterial chemoreceptor reflex in anesthetized rats.

Chronic heart failure (CHF) is well known to be associated with both an enhanced chemoreceptor reflex and an augmented cardiac "sympathetic afferent reflex" (CSAR). The augmentation of the CSAR may play an important role in the enhanced chemoreceptor reflex in the CHF state because the same central areas are involved in the sympathetic outputs of both reflexes. We determined whether chemical and electrical stimulation of the CSAR augments chemoreceptor reflex function in normal rats. Under anesthesia, renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded. The chemoreceptor reflex was tested by unilateral intra-carotid artery bolus injection of potassium cyanide (KCN) and nicotine. We found that 1) left ventricular epicardial application of capsaicin increased the pressor responses and the RSNA responses to chemoreflex activation induced by both KCN and nicotine; 2) when the central end of the left cardiac sympathetic nerve was electrically stimulated, both the pressor and the RSNA responses to chemoreflex activation induced by KCN were increased; 3) pretreatment with intracerebroventricular injection of losartan (500 nmol) completely prevented the enhanced chemoreceptor reflex induced by electrical stimulation of the cardiac sympathetic nerve; and 4) bilateral microinjection of losartan (250 pmol) into the nucleus tractus solitarii (NTS) completely abolished the enhanced chemoreceptor reflex by epicardial application of capsaicin. These results suggest that both the chemical and electrical stimulation of the CSAR augments chemoreceptor reflex and that central ANG II, specially located in the NTS, plays a major role in these reflex interactions.     

Evidence for alpha-2 adrenoreceptor modulation of arterial chemoreflexes in the caudal solitary nucleus of the rat

The caudal region of the nucleus of the solitary tract (cNTS) is the primary central termination site for arterial chemoreceptor afferents originating from the carotid body. The purpose of the present study was to investigate the role of endogenous activation of alpha-2 adrenoreceptors in the cNTS on arterial chemoreflex function. Arterial chemoreflex responses to intravenous injections of potassium cyanide (KCN; 75 microg/kg) were recorded before and following blockade of alpha-2 adrenoreceptors in the cNTS of urethane-anesthetized rats. KCN alone elicited a reflex increase in arterial pressure, renal sympathetic nerve activity, and respiration. After bilateral cNTS microinjection of alpha-2 receptor antagonists (2 nmol idazoxan or 0.2 nmol yohimbine), arterial chemoreflex responses were markedly attenuated. Attenuation of chemoreflex function was not accompanied by any significant change in resting blood pressure or respiratory rate. The results suggest that the endogenous activation of alpha-2 adrenoreceptors facilitates central processing of chemoreceptor afferent inputs in the cNTS of the rat.     

Chronic intermittent hypoxia alters NMDA and AMPA-evoked currents in NTS neurons receiving carotid body chemoreceptor inputs

Chronic exposure to intermittent hypoxia (CIH) has been used in animals to mimic the arterial hypoxemia that accompanies sleep apnea. Humans with sleep apnea and animals exposed to CIH have elevated blood pressures and augmented sympathetic nervous system responses to acute exposures to hypoxia. To test the hypothesis that exposure to CIH alters neurons within the nucleus of the solitary tract (NTS) that integrate arterial chemoreceptor afferent inputs, we measured whole cell currents induced by activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors in enzymatically dispersed NTS neurons from normoxic (NORM) and CIH-exposed rats (alternating cycles of 3 min at 10% O2 followed by 3 min at 21% O2 between 8 AM and 4 PM for 7 days). To identify NTS neurons receiving carotid body afferent inputs the anterograde tracer 4- (4-(dihexadecylamino)styryl-N-methylpyridinum iodide (DiA) was placed onto the carotid body 1 wk before exposure to CIH. AMPA dose-response curves had similar EC50 but maximal responses increased in neurons isolated from DiA-labeled CIH (20.1 +/- 0.8 microM, n = 9) compared with NORM (6.0 +/- 0.3 microM, n = 8) rats. NMDA dose-response curves also had similar EC50 but maximal responses decreased in CIH (8.4 +/- 0.4 microM, n = 8) compared with NORM (19.4 +/- 0.6 microM, n = 9) rats. These results suggest reciprocal changes in the number and/or conductance characteristics of AMPA and NMDA receptors. Enhanced responses to AMPA receptor activation could contribute to enhanced chemoreflex responses observed in animals exposed to CIH and humans with sleep apnea.     

Hypoxia transduction by carotid body chemoreceptors in mice lacking dopamine D(2) receptors.

Hypoxia-induced dopamine (DA) release from carotid body (CB) glomus cells and activation of postsynaptic D(2) receptors have been proposed to play an important role in the neurotransmission process between the glomus cells and afferent nerve endings. To better resolve the role of D(2) receptors, we examined afferent nerve activity, catecholamine content and release, and ventilation of genetically engineered mice lacking D(2) receptors (D(2)(-/-) mice). Single-unit afferent nerve activities of D(2)(-/-) mice in vitro were significantly reduced by 45% and 25% compared with wild-type (WT) mice during superfusion with saline equilibrated with mild hypoxia (Po(2) approximately 50 Torr) or severe hypoxia (Po(2) approximately 20 Torr), respectively. Catecholamine release in D(2)(-/-) mice was enhanced by 125% in mild hypoxia and 75% in severe hypoxia compared with WT mice, and the rate of rise was increased in D(2)(-/-) mice. We conclude that CB transduction of hypoxia is still present in D(2)(-/-) mice, but the response magnitude is reduced. However, the ventilatory response to acute hypoxia is maintained, perhaps because of an enhanced processing of chemoreceptor input by brain stem respiratory nuclei.     

Function of the rat carotid body chemoreceptors in ageing

Some age-related deficits in the ventilatory responses have been attributed to a decline in the functionality of the carotid body (CB) arterial chemoreceptors, but a systematic study of the CB function in ageing is lacking. In rats aged 3-24 months, we have performed quantitative morphometry on specific chemoreceptor tissue, assessed the function of chemoreceptor cells by measuring the content, synthesis and release of catecholamines (a chemoreceptor cell neurotransmitter) in normoxia and hypoxia, and determined the functional activity of the intact organ by measuring chemosensory activity in the carotid sinus nerve (CSN) in normoxia, hypoxia and hypercapnic acidosis. We found that with age CBs enlarge, but at the same time there is a concomitant decrease in the percentage of chemoreceptor tissue. CB content and turnover time for their catecholamines increase with age. Hypoxic stimulation of chemoreceptor cells elicits a smaller release of catecholamines in rats after 12 months of age, but a non-specific depolarizing stimulus elicits a comparable release at all ages. In parallel, there was a marked decrease in the responsiveness to hypoxia, but not to an acidic-hypercapnic stimulus, assessed as chemosensory activity in the CSN. We conclude that in aged mammals chemoreceptor cells become hypofunctional, leading to a decreased peripheral drive of ventilation.     

Intermittent hypoxia and activation of inflammatory molecular pathways in OSAS

Obstructive sleep apnoea syndrome (OSAS) represents a highly prevalent disease and is recognized as a risk factor for the development of various cardiovascular disorders. The pathogenesis of cardiovascular complications in OSAS is not completely understood, but the unique form of hypoxia with repetitive short cycles of desaturation followed by rapid reoxygenation termed intermittent hypoxia (IH) is likely to play a significant role. There is increasing evidence that IH leads to a preferential activation of inflammatory over adaptive pathways. This promotes activation of various inflammatory cells, particularly lymphocytes and monocytes, with the downstream consequence of expression of pro-inflammatory cytokines, chemokines and adhesion molecules that may contribute to endothelial dysfunction. This review provides a critical analysis of the current evidence of inflammatory mechanisms initiated by IH that may contribute to the cardiovascular pathogenesis in OSAS.     

Periods of intermittent hypoxic apnea can alter chemoreflex control of sympathetic nerve activity in humans

Obstructive sleep apnea is associated with sustained elevation of muscle sympathetic nerve activity (MSNA) and altered chemoreflex control of MSNA, both of which likely play an important role in the development of hypertension in these patients. Additionally, short-term exposure to intermittent hypoxic apneas can produce a sustained elevation of MSNA. Therefore, we tested the hypothesis that 20 min of intermittent hypoxic apneas can alter chemoreflex control of MSNA. Twenty-one subjects were randomly assigned to one of three groups (hypoxic apnea, hypercapnic hypoxia, and isocapnic hypoxia). Subjects were exposed to 30 s of the perturbation every minute for 20 min. Chemoreflex control of MSNA was assessed during baseline, 1 min posttreatment, and every 15 min throughout 180 min of recovery by the MSNA response to a single hypoxic apnea. Recovery hypoxic apneas were matched to a baseline hypoxic apnea with a similar nadir oxygen saturation. A significant main effect for chemoreflex control of MSNA was observed after 20 min of intermittent hypoxic apneas (P <0.001). The MSNA response to a single hypoxic apnea was attenuated 1 min postexposure compared with baseline (P <0.001), became augmented within 30 min of recovery, and remained augmented through 165 min of recovery (P <0.05). Comparison of treatment groups revealed no differences in the chemoreflex control of MSNA during recovery (P=0.69). These data support the hypothesis that 20 min of intermittent hypoxic apneas can alter chemoreflex control of MSNA. Furthermore, this response appears to be mediated by hypoxia.     

Altered nitric oxide mechanism within the paraventricular nucleus contributes to the augmented carotid body chemoreflex in heart failure

Our previous study demonstrated a contribution of the paraventricular nucleus (PVN) of the hypothalamus in the processing of the carotid body (CB) chemoreflex. Nitric oxide (NO) (within the PVN), known to modulate autonomic function, is altered in rats with heart failure (HF). Therefore, the goal of the present study was to examine the influence of endogenous and exogenous NO within the PVN on the sympathoexcitatory component of the peripheral chemoreflex in normal and HF states. We measured mean arterial blood pressure, heart rate, renal sympathetic nerve activity (RSNA), and phrenic nerve activity (PNA) in sham-operated and HF rats (6-8 wk after coronary artery ligation) after incremental doses of potassium cyanide (25-100 mug/kg iv). There was potentiation of the reflex responses in HF compared with sham-operated rats. Bilateral microinjection of an inhibitor of NO synthase, N(G)-monomethyl-l-arginine (50 pmol), into the PVN augmented the RSNA and PNA response to peripheral chemoreceptor stimulation in sham-operated rats but had no effect in HF rats. Conversely, bilateral microinjection of a NO donor, sodium nitroprusside (50 nmol), into the PVN attenuated the RSNA response of the peripheral chemoreflex in sham-operated rats but to a smaller extent in HF rats. These data indicate that 1) NO within the PVN plays an important role in the processing of the CB chemoreflex and 2) there is an impairment of the NO function within the PVN of HF rats, which contributes to an augmented peripheral chemoreflex and subsequent elevation of sympathetic activity in HF.     

Cardiovascular responses to peripheral chemoreflex activation and comparison of different methods to evaluate baroreflex gain in conscious mice using telemetry

Peripheral chemoreceptors located in the carotid bodies are the primary sensors of systemic hypoxia. Although the pattern of responses elicited by peripheral chemoreceptor activation is well established in rats, lambs, and rabbits, the cardiovascular responses to peripheral chemoreflex activation in conscious mice have not been delineated. Here we report that stimulation of peripheral chemoreceptors by potassium cyanide (KCN) in conscious mice elicits a unique biphasic response in blood pressure that is characterized by an initial and robust rise followed by a decrease in blood pressure, which is accompanied by a marked reduction in heart rate. The depressor and bradycardic responses to KCN were abolished by muscarinic receptor blockade with atropine, and the pressor response was abolished by alpha-adrenergic receptor blockade with prazosin, suggesting that vagal and sympathetic drive to the heart and sympathetic drive to the vasculature mediate these cardiovascular responses. These studies characterized the chemoreflex in conscious mice and established the reliability of using them for studying hypoxia-related diseases such as obstructive sleep apnea. In another series of experiments, two methods for analyzing baroreflex sensitivity were compared: the classical pharmacological approach using phenylephrine and sodium nitroprusside (i.e., the Oxford technique) or the sequence method for analyzing spontaneous baroreflex activity. Our findings indicate that both methods are reliable, and the sequence method certainly has its benefits as a predictive tool in the context of long-term noninvasive studies using telemetry. However, for absolute determination of baroreflex function, analysis of spontaneous baroreflex activity should be complemented by the classical pharmacological method.     

Chemoreflexive drive of ventilation and noradrenaline stimulus in man]

O2 chemoreflex drive of ventilation was studied before and after an intravenous infusion of L-norepinephrine (9 microgram/min), inducing a plasmatic hormone concentration similar to that obtained during submaximal exercise. The ventilation increasing rapidly at the beginning of the infusion was stabilized after 30 min : the ventilation was two times the reference value. The O2 chemoreflex drive of ventilation increased during norepinephrine infusion. When man was transiently switched from hypoxia to pure O2 (O2 test) the maximal fall of ventilation was two times the reference response. This increase in the chemoreflex drive, although the physico-chemical blood state was unchanged, may be explained by a norepinephrine chemoreceptor sensitization. Such a mechanism could partly explain the increase of O2 chemoreflex drive observed during muscular exercise.     

Raphe serotonergic neurons modulate genioglossus corticomotor activity in intermittent hypoxic rats

Background

Genioglossus activity is greater during wakefulness but decreases to a weaker state during sleep in obstructive sleep apnea syndrome (OSAS) patients, compared to healthy subjects. Previous studies suggested that the corticomotor control of the genioglossus was modified in OSAS patients. Intermittent hypoxia (IH), the typical pathophysiological change in OSAS, can induce genioglossus facilitation. The serotonergic neurons of the raphe dorsal (DRN) and magnus nuclei (RMg) are responsive to hypoxia and play important roles in the control of the genioglossus. However, it remains unknown whether DRN and RMg serotonergic neurons are responsible for the facilitated corticomotor activity of the genioglossus during IH. This study explored the influence of IH on the corticomotor activity of the genioglossus by transcranial magnetic stimulation (TMS), and the role of DRN and RMg serotonergic neurons in this effect.

Methods

Rats were exposed to IH and divided into two groups. In one group, anti-SERT-SAP was microinjected into the DRN and RMg respectively to kill serotonergic neurons. In the other group, artificial cerebrospinal fluid (ACSF) was injected. Comparisons were conducted between the two groups during four weeks of IH and four weeks after IH.

Results

Compared to the corresponding ACSF-injected group, the DRN lesion group and RMg lesion group showed longer TMS latencies and lower amplitudes during IH from the 1^st to the 28^th day. After 28 days of IH, longer latencies and lower amplitudes were seen only in the DRN lesion group.

Conclusion

These results indicate that DRN and RMg serotonergic neurons play different roles in the facilitation of genioglossus corticomotor activity induced by IH.     

Influence of pontine A5 region on renal sympathetic nerve activity in conscious rabbits

The effects of inhibiting the neural activity in the pontine A5 region on renal sympathetic responses to baroreflex and/or chemoreflex activation were examined in conscious rabbits. Eight rabbits were chronically instrumented with guide cannulas for bilateral microinjections into the A5 area and an electrode for measuring renal sympathetic nerve activity (RSNA). Baroreflex curves were obtained under conditions of normoxia and hypoxia (10% O(2) + 3% CO(2)) after injections into the A5 region of the GABA receptor agonist muscimol or vehicle solution. Under normoxia, injections of muscimol did not affect resting RSNA or blood pressure but increased the range of the RSNA baroreflex by 24 and 33% at doses of 175 or 875 pmol, respectively, without affecting the reflex gain. Hypoxia alone increased resting RSNA by 63%, as well as the range and gain of the RSNA baroreflex by 53 and 89%, respectively, without affecting blood pressure. However, under hypoxia, muscimol increased resting RSNA by 37 and 47% but decreased the gain of the RSNA baroreflex by 19 and 34% at doses of 175 or 875 pmol, respectively, without affecting the reflex range. The effects of muscimol on RSNA were mediated via changes in the amplitude of the sympathetic bursts, whereas burst frequency remained unaffected. These data suggest that the A5 region has a little tonic influence on RSNA in conscious rabbits but serves to limit the renal sympathetic responses to baroreceptor unloading or chemoreceptor stimulation. The different changes in the baroreflex range and gain evoked by muscimol under normoxia and hypoxia indicate that the A5 modulatory action may depend on the activity of the afferent inputs to this region.     

Day-night variations of serum interleukin-6 in patients with severe obstructive sleep apnea syndrome before and after continuous positive airway pressure (CPAP)

Obstructive sleep apnea syndrome (OSAS) causes intermittent hypoxia and increases in sympathetic activity and contributes to cardiovascular disorders. Interleukin-6 (IL-6) is one of the important proinflammatory cytokines. We examined the levels of serum IL-6 concentrations in nine patients with severe OSAS at four different clock times during the 24 h before and after three months of continuous positive airway pressure (CPAP) therapy. Serum IL-6 levels were significantly reduced after CPAP therapy by 46% (6.2+/-1.0 vs. 3.3+/-0.4 pg/ml, p<0.005). No significant 24 h variation of serum IL-6 in severe OSAS patients was found before CPAP; however, a significant 24 h variation of serum IL-6 was found after CPAP. Intermittent hypoxia during sleep may contribute to systemic inflammation and result in an elevation of serum IL-6 in severe OSAS patients.     

Day‐Night Variations of Serum Interleukin‐6 in Patients with Severe Obstructive Sleep Apnea Syndrome before and after Continuous Positive Airway Pressure (CPAP)

Obstructive sleep apnea syndrome (OSAS) causes intermittent hypoxia and increases in sympathetic activity and contributes to cardiovascular disorders. Interleukin‐6 (IL‐6) is one of the important proinflammatory cytokines. We examined the levels of serum IL‐6 concentrations in nine patients with severe OSAS at four different clock times during the 24 h before and after three months of continuous positive airway pressure (CPAP) therapy. Serum IL‐6 levels were significantly reduced after CPAP therapy by 46% (6.2±1.0 vs. 3.3±0.4 pg/ml, p<0.005). No significant 24 h variation of serum IL‐6 in severe OSAS patients was found before CPAP; however, a significant 24 h variation of serum IL‐6 was found after CPAP. Intermittent hypoxia during sleep may contribute to systemic inflammation and result in an elevation of serum IL‐6 in severe OSAS patients.     

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.