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(Circulation. 1999;99:1183-1189.)
© 1999 American Heart Association, Inc.

Clinical Investigation and Reports

Selective Potentiation of Peripheral Chemoreflex Sensitivity in Obstructive Sleep Apnea

Krzysztof Narkiewicz, MD, PhD; Philippe J. H. van de Borne, MD, PhD; Catherine A. Pesek, DO; Mark E. Dyken, MD; Nicola Montano, MD, PhD; Virend K. Somers, MD, PhD

From the Cardiovascular Division, Department of Internal Medicine (K.N., P.J.H.v.d.B., C.A.P., V.K.S.) and Department of Neurology (M.E.D.), University of Iowa College of Medicine, Iowa City, and Centro L.I.T.A. Vialba, Centro Ricerche Cardiovascolari, CNR, Medicina Interna II, Ospedalè L. Sacco, Universitá degli Studi di Milano, Italy (N.M.).

Correspondence to Virend Somers, MD, PhD, Cardiovascular Division, Department of Internal Medicine, University of Iowa, 200 Hawkins Dr, Iowa City, IA 52242. E-mail virend-somers{at}uiowa.edu

	Abstract

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Background—The chemoreflexes are an important mechanism for regulation of both breathing and autonomic cardiovascular function. Abnormalities in chemoreflex mechanisms may be implicated in increased cardiovascular stress in patients with obstructive sleep apnea (OSA). We tested the hypothesis that chemoreflex function is altered in patients with OSA.

Methods and Results—We compared ventilatory, sympathetic, heart rate, and blood pressure responses to hypoxia, hypercapnia, and the cold pressor test in 16 untreated normotensive patients with OSA and 12 normal control subjects matched for age and body mass index. Baseline muscle sympathetic nerve activity (MSNA) was higher in the patients with OSA than in the control subjects (43±4 versus 21±3 bursts per minute; P<0.001). During hypoxia, patients with OSA had greater increases in minute ventilation (5.8±0.8 versus 3.2±0.7 L/min; P=0.02), heart rate (10±1 versus 7±1 bpm; P=0.03), and mean arterial pressure (7±2 versus 0±2 mm Hg; P=0.001) than control subjects. Despite higher ventilation and blood pressure (both of which inhibit sympathetic activity) in OSA patients, the MSNA increase during hypoxia was similar in OSA patients and control subjects. When the sympathetic-inhibitory influence of breathing was eliminated by apnea during hypoxia, the increase in MSNA in OSA patients (106±20%) was greater than in control subjects (52±23%; P=0.04). Prolongation of R-R interval with apnea during hypoxia was also greater in OSA patients (24±6%) than in control subjects (7±5%) (P=0.04). Autonomic, ventilatory, and blood pressure responses to hypercapnia and the cold pressor test in OSA patients were not different from those observed in control subjects.

Conclusions—OSA is associated with a selective potentiation of autonomic, hemodynamic, and ventilatory responses to peripheral chemoreceptor activation by hypoxia.

Key Words: nervous system • sleep • blood pressure • heart rate • hypoxia

	Introduction

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Peripheral chemoreceptors, located in the carotid bodies, respond primarily to hypoxia.^{1 2} Central chemoreceptors, located on the ventral surface of the medulla, respond primarily to hypercapnia.³ Peripheral and central chemoreceptors are the dominant reflex control mechanisms regulating ventilatory responses to changes in arterial oxygen and carbon dioxide content.⁴

Both sets of chemoreceptors also have powerful effects on neural circulatory control.^{5 6 7 8 9} Peripheral chemoreceptors elicit increases in sympathetic nerve traffic, with consequent increases in blood pressure.^{10 11 12} Peripheral chemoreflex activation in the absence of breathing (the diving reflex) increases sympathetic vasoconstrictor activity to peripheral blood vessels and also simultaneously increases cardiac vagal activity, causing bradycardia.^{13 14 15} Central chemoreceptor activation increases sympathetic nerve traffic and blood pressure.¹¹ Increased blood pressure and increased minute ventilation both inhibit the sympathetic response to chemoreflex activation.^{11 12 16}

Patients with obstructive sleep apnea (OSA) experience repeated prolonged episodes of cessation of breathing during sleep due to upper airway occlusion during inspiration.¹⁷ These patients also have high sympathetic activity, even during normoxic wakefulness.^{18 19 20} The chemoreflexes are an important mechanism for regulation of both breathing and autonomic cardiovascular function. Abnormalities in chemoreflex mechanisms may therefore be implicated in increased cardiovascular stress in patients with OSA.²¹

Chemoreflex activation elicits a number of cardiorespiratory responses, with complex interactions between the responses themselves. Therefore, to define any abnormalities in chemoreflex function, it is important that key components of the integrated chemoreflex response be considered. Previous studies examining chemoreflex responses in patients with OSA have examined primarily the ventilatory responses to hypoxia. These studies have reported conflicting results, showing either decreased,^{22 23} increased,^{24 25} or normal responses²⁶ to hypoxia in patients with OSA. Hypertension,²⁷ obesity,²⁸ and age²⁹ significantly influence chemoreflex sensitivity. Furthermore, the effects of treatment with medications and/or continuous positive airway pressure on chemoreflex function are unpredictable. Thus, the absence of control for these variables may be implicated in the inconsistency in the literature. In addition, even asymptomatic obese individuals have a high incidence of occult significant OSA.³⁰ Thus, undiagnosed OSA in apparently normal control subjects may inadvertently obscure any distinctive chemoreflex abnormalities in OSA per se.

We tested the hypothesis that chemoreflex function is altered in OSA, independent of factors such as hypertension, obesity, and age. We measured autonomic, ventilatory, and hemodynamic responses to peripheral chemoreceptor activation by hypoxia and to central chemoreceptor activation by hypercapnia in newly diagnosed, never-treated patients with OSA who were free of any other known disease and were on no medications. These responses were compared with those obtained in normal control subjects closely matched for age and body mass index, in whom occult OSA was excluded by complete overnight polysomnographic study. To ensure that any abnormalities in chemoreflex function were specific to the chemoreflexes and did not represent a nonspecific generalized abnormality in response to excitatory stimuli, we also compared the responses to the cold pressor test, which served as an internal control.³¹

	Methods

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Subjects
To avoid the confounding effects of comorbidities and treatment, we studied only patients with newly diagnosed OSA who were normotensive, free of any other diseases, and on no medications and had never been treated for OSA. Of 200 sleep apneic patients screened, 16 (13 men) fulfilled the criteria and agreed to participate in the study (mean age, 42±2 years; mean body mass index, 33±2 kg/m²). Severity of OSA was defined on the basis of the apnea-hypopnea index, indicating the number of respiratory irregularities per sleep-hour. The 16 sleep apneic patients had an apnea-hypopnea index of 38±8 events per hour.

We also studied 12 healthy control subjects (9 men) matched for age and body mass index (mean age, 40±3 years; mean body mass index, 33±2 kg/m²). Sleep disordered breathing was excluded in control subjects by complete overnight polysomnographic studies.

Informed written consent was obtained from all subjects. The study was approved by the Institutional Human Subjects Review Committee.

Measurements
Heart rate was measured continuously by an ECG. Blood pressure was measured each minute by an automatic sphygmomanometer (Life Stat 200, Physio-Control Corp). Oxygen saturation was monitored with a pulse oximeter (Nellcor Inc). End-tidal CO₂ was monitored with a Hewlett-Packard 47210A Capnometer. Minute ventilation was determined with a KL Engineering S430 monitor. Breathing was via a mouthpiece with a nose clip to ensure exclusive mouth breathing.

Sympathetic nerve activity to muscle was recorded continuously by multiunit recordings of postganglionic sympathetic activity to muscle circulation, measured from a nerve fascicle in the peroneal nerve posterior to the fibular head, as described previously.³²

Protocol and Procedures
Subjects were studied in the supine position. The protocol used to determine chemoreflex responses to isocapnic hypoxia and hyperoxic hypercapnia was identical to that used in previous studies.^{11 12 16} Subjects were exposed to a hypoxic gas mixture to induce peripheral chemoreflex activation (10% O₂ in N₂ with CO₂ titrated to maintain isocapnia) and a hypercapnic gas mixture to induce central chemoreflex activation (7% CO₂ /93% O₂). During hypoxic stimulation of peripheral chemoreceptors, perturbation of central chemoreceptors was minimized by the maintenance of isocapnia.¹² During hypercapnic stimulation of central chemoreceptors, perturbation of peripheral chemoreceptors was minimized by hyperoxia.¹¹ The sequence of hypoxic and hypercapnic interventions was randomized. At least 15 minutes separated the end of one intervention from the beginning of the next.

Baseline measurements were taken during a 5-minute period of stable ventilation while subjects breathed room air with a mouthpiece. Then, by use of a 3-way valve, the subjects were exposed to either the hypoxic or hypercapnic stressors for 3 minutes. Average values for the 3-minute period of gas exposure were used in comparison to measurements obtained at baseline. At the end of the gas exposure, the subjects underwent a brief period of voluntary end-expiratory apnea to examine the sympathetic responses to chemoreflex activation in the absence of the inhibitory influence of the thoracic afferents. Two patients with OSA were unable to comfortably tolerate the stress of hypoxia and/or hypercapnia. Consequently, we completed studies examining the effects of hypoxia in 15 patients with OSA and the effects of hypercapnia in 14 patients with OSA. Ten control subjects and 12 patients with OSA underwent a subsequent cold pressor test. The cold pressor test is a stimulus for ventilation and sympathetic excitation and involves immersing the subject's hand into ice water for 2 minutes.^{31 33}

Analyses
Sympathetic bursts were identified by a careful inspection of the voltage neurogram. The amplitude of each burst was determined, and sympathetic activity was calculated as bursts per minute multiplied by mean burst amplitude and expressed as units per minute. The intraobserver and interobserver variabilities in our laboratory are 4.3±0.3%³⁴ and 5.4±0.5%,³⁵ respectively. Measurement of nerve activity at baseline before each intervention was expressed as 100%. For the apneas, the first 10 seconds were analyzed, because all patients and control subjects were able to maintain apnea for at least 10 seconds at the end of the hypoxic and hypercapnic exposures. Changes in sympathetic nerve activity and maximal R-R prolongation during apnea were expressed as a percentage increase from the preceding minute (eg, last minute of hypoxia or hypercapnia).

Demographic data and baseline characteristics were compared by an unpaired t test. Responses to hypoxia, hypercapnia, and the cold pressor test were analyzed by repeated-measures ANOVA with time (baseline versus intervention) as the within factor and group (the control subjects versus the patients with OSA) as the between factor. The key variable was the group-by-time interaction. Data are presented as mean±SEM. A value of P<0.05 was considered significant.

	Results

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Resting Values
Table 1 shows baseline characteristics of the patients with OSA and control subjects during free breathing of room air. Oxygen saturation, mean arterial pressure (MAP), and heart rate in patients with OSA were similar to those observed in the normal obese subjects without OSA. Baseline muscle sympathetic nerve activity (MSNA) was markedly elevated in the patients with OSA compared with the control subjects (43±4 versus 21±3 bursts per minute; P<0.001).

View this table: [in this window] [in a new window]   Table 1. Resting Measurements in Free-Breathing Normal Control Subjects and Patients With OSA

Effects of Hypoxia
The change in oxygen saturation during hypoxia was similar in patients with OSA and in control subjects (Table 2, Figures 1 and 2). The control subjects and the patients with OSA both showed increases in minute ventilation and heart rate during hypoxia. However, the increase in heart rate (P=0.03) and minute ventilation (P=0.02) was significantly greater in patients with OSA (Table 2, Figures 1 and 2). MAP in the control subjects did not increase during hypoxia (Table 2, Figure 2). By contrast, MAP increased by 7.1±1.6 mm Hg during hypoxia in patients with OSA, and the group-by-time interaction was highly significant (P=0.001) (Table 2, Figure 2).

View this table: [in this window] [in a new window]   Table 2. Effects of Hypoxia in Normal Subjects and in Patients With OSA

View larger version (29K): [in this window] [in a new window]   Figure 1. ECG tracings and sympathetic neurograms at baseline, during minute 3 of hypoxia, and during 10 seconds of apnea at end of minute 3 of hypoxia. Recordings are shown in a normal control subject (top) and in a patient with OSA (bottom). Despite a similar reduction in oxygen saturation, hypoxia produced greater increases in heart rate (HR), minute ventilation (VE), and MAP in patient with OSA. Hypoxia increased sympathetic activity both in control subject and in patient with OSA, even though changes in blood pressure and minute ventilation (both of which inhibit MSNA) were greater in OSA patient. When autonomic inhibitory influence of breathing was eliminated by apnea, increase in sympathetic nerve activity in patient with OSA was greater than that in control subject and was accompanied by prolongation of R-R interval.

View larger version (19K): [in this window] [in a new window]   Figure 2. Changes () in oxygen saturation (O2 sat), minute ventilation (VE), MAP, and MSNA during hypoxia in control subjects () and in patients with OSA (). Similar degrees of oxygen desaturation induced greater increases in minute ventilation and MAP in patients with OSA. Despite higher VE and MAP in OSA patients, MSNA response in OSA patients was still comparable to that seen in control subjects. *P<0.05 for group-by-time interaction. Data are mean±SEM.

Despite higher minute ventilation and higher blood pressure during hypoxia in the OSA patients, hypoxia induced similar percentage increases in MSNA in the control subjects and in the patients with OSA (Figure 1, Figure 3). The magnitude of these increases during breathing was not significantly different between the 2 groups (Table 2, Figure 2).

View larger version (27K): [in this window] [in a new window]   Figure 3. Percent changes of MSNA and R-R interval with apnea during hypoxia in control subjects (open bars) and in patients with OSA (hatched bars). Increase in MSNA and R-R interval with apnea was significantly greater in patients with OSA (*P<0.05). Data are mean±SEM.

Effects of Apnea During Hypoxia
When the inhibitory influence of breathing during hypoxia was eliminated by apnea, the increase in sympathetic nerve activity in patients with OSA was greater than in the control subjects (Figures 1 and 3). Sympathetic nerve activity during apnea increased by 52±23% in the normal subjects and by 106±20% in the patients with OSA (P=0.04). Prolongation of R-R interval during apnea was greater in the patients with OSA (24±6%) than in the control subjects (7±5%; P=0.04) (Figure 3).

Effects of Hypercapnia
The magnitude of the ventilatory, heart rate, blood pressure, and MSNA responses to hypercapnia was similar in the control subjects and patients with OSA (Table 3). Changes in MSNA and R-R interval in response to apnea during hypercapnia were also similar in the 2 groups (data not shown).

View this table: [in this window] [in a new window]   Table 3. Effects of Hypercapnia in Normal Subjects and in Patients With OSA

Effects of the Cold Pressor Test
Autonomic, ventilatory, and blood pressure changes during the cold pressor test in patients with OSA were not significantly different from those observed in the control subjects (Figure 4).

View larger version (16K): [in this window] [in a new window]   Figure 4. Changes () in heart rate (HR), minute ventilation (VE), MAP, and MSNA during cold pressor test (CPT) in control subjects (; n=10) and in patients with OSA (; n=12). Ventilatory, autonomic, and blood pressure changes during cold pressor test in patients with OSA were not significantly different from those observed in control subjects. Data are mean±SEM.

	Discussion

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The novel findings of this study are, first, that the peripheral chemoreflex response to hypoxia is potentiated in patients with OSA. This is evident in the increased ventilatory, pressor, and heart rate responses to hypoxic breathing. Because the ventilatory response to hypoxia inhibits and may therefore obscure the autonomic chemoreflex responses, it is only during apnea that the potentiated sympathetic response (to peripheral blood vessels) and vagal response (to the heart) become evident. Second, this chemoreflex abnormality is selective for the peripheral chemoreflex. There is preservation of the normal responses to both central chemoreflex activation and the cold pressor test.

During hypoxic breathing, ventilation and blood pressure increased substantially in OSA patients compared with normal control subjects. Both of these act as powerful restraints on the sympathetic response to hypoxia.^{12 16} When blood pressure in normal subjects is increased (by intravenous phenylephrine) to levels similar to the increase observed in sleep apneic patients exposed to hypoxia, the sympathetic response to hypoxia is eliminated in normal subjects.¹⁶ Nevertheless, in the present study, the increase in sympathetic activity in OSA patients during hypoxia was still comparable to that seen in control subjects, despite the higher blood pressures and higher ventilation. Thus, in OSA patients, the chemoreflex appears to be a potent mechanism for sympathetic activation, overriding the combined restraining influences of increased blood pressure and increased ventilation. This suggests, but does not prove, that not only the ventilatory but also the chemoreflex-mediated sympathetic autonomic response to hypoxia is augmented in OSA. The proof is evident during apnea, when the vagolytic and sympathetic-inhibitory influences of breathing are eliminated.⁵ During apnea, an enhanced peripheral sympathetic response and an enhanced vagal bradycardic response are manifest. Thus, there is a global potentiation of the peripheral chemoreflex response in OSA, affecting both the ventilatory and autonomic efferent limbs of the reflex. Potentiated ventilatory²⁷ and sympathetic³⁶ responses to hypoxia were demonstrated previously in patients with hypertension. However, the enhanced chemoreflex responses we report are evident in the absence of higher blood pressure in the OSA patients (Figure 1).

Previous studies examining the pressor response to hypoxia in OSA have yielded conflicting results.^{24 26 37} Our data show clearly that the blood pressure increase during hypoxia is markedly exaggerated in OSA patients. These findings are important in understanding the absence of any nocturnal blood pressure decline in untreated sleep apneics, in whom repetitive apneic episodes elicit surges in blood pressure throughout the night.²⁰ Furthermore, pressor responses and consequent baroreflex resetting to a higher set point may be implicated in the development of sustained hypertension in these patients.^{37 38} The exaggerated pressor response to hypoxia in OSA is explained in part by the greater increase in heart rate. However, other factors, such as impaired hypoxic vasodilator effects, cannot be excluded. The absence of any increased pressor response to the cold pressor test suggests that that the increased pressor response to hypoxia in OSA is not explained by any nonspecific exaggeration of the pressor response to excitatory stimuli generally.

Important strengths of this study include, first, that both ventilatory and cardiovascular responses to hypoxia were studied and that both these responses were shown to be potentiated in OSA patients. Second, all OSA patients were newly diagnosed, never treated, and free of any other known disease. Third, control subjects were closely matched for age and body mass index. Control subjects also underwent complete overnight polysomnographic study to exclude occult undiagnosed OSA, which is highly prevalent even in asymptomatic, seemingly normal, obese subjects.³⁰ Fourth, all participants in this study were on no medications. Thus, the potential influence of confounding variables, such as hypertension, age, obesity, treatment (either with continuous positive airway pressure or medications), and occult OSA, in control subjects was eliminated.

Possible limitations of our study include, first, that chemoreflex measurements were obtained during daytime wakefulness. Nevertheless, the autonomic chemoreflex responses we report are very similar to those observed during nighttime sleep in patients with OSA. During sleep, these patients experience sympathetic activation in response to oxygen desaturation, with consequent surges in blood pressure.²⁰ Patients with OSA also demonstrate a cyclical variation of nocturnal heart rate, with progressive bradycardia and often bradyarrhythmias.^{39 40} The pattern of heart rate during sleep apneic events correlates very closely with changes seen with apnea during hypoxia while awake.⁴¹ Second, we did not address the possible influence of familial aggregation of OSA^{42 43 44} on chemoreflex function. There may be a subset of patients with familial OSA who have a reduced ventilatory response to hypoxia.⁴⁴ Third, our data do not address the question of whether an enhanced peripheral chemoreflex sensitivity to hypoxia is implicated in the pathogenesis of OSA. Increased chemoreflex sensitivity may be merely an adaptive response to repetitive apneas during sleep.

A recent study by Kimoff and colleagues⁴⁵ speaks directly to this question. These investigators devised a dog model closely simulating OSA in humans.^{46 47} They induced repetitive nocturnal airway obstructions in previously normal dogs, closely mimicking the OSA syndrome. After 3 months of simulated OSA, the chemoreflex responses to hypoxia in these dogs were strikingly reduced during wakefulness and were also reduced significantly during sleep.⁴⁵ Therefore, OSA would be expected to result in a reduction in chemoreflex sensitivity. The findings of enhanced chemoreflex sensitivity in our patients are therefore unlikely to be explained as an adaptive response to repetitive apneic events.

In conclusion, these data demonstrate a specific potentiation of autonomic and ventilatory responses to peripheral chemoreceptor activation in OSA. By contrast, responses to central chemoreceptor activation and responses to the nonspecific excitatory cold pressor stimulus are preserved. We speculate that this abnormality in the peripheral chemoreceptor response may be implicated in increased cardiovascular stress and morbidity in patients with OSA.

	Acknowledgments

 
Dr Narkiewicz, a visiting research scientist from the Department of Hypertension and Diabetology, Medical School of Gdansk, Poland, is a recipient of an International Research John E. Fogarty Fellowship (NIH 3F05-TW-05200) and a Perkins Memorial Award from the American Physiological Society. These studies were also supported by an American Heart Association Established Investigator Grant, National Institutes of Health grant HL-14388, and a Sleep Academic Award from the National Institutes of Health (Dr Somers). We thank Diane Davison, RN, MA, for technical assistance.

Received July 28, 1998; revision received October 28, 1998; accepted November 23, 1998.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Wade JG, Larson CP Jr, Hickey RF, Ehrenfeld WK, Severinghaus JW. Effect of carotid endartectomy on carotid chemoreceptor and baroreceptor function in man. N Engl J Med. 1970;282:823–829.
   
2. Lugliani RB, Whipp BJ, Seard C, Wasserman K. Effect of bilateral carotid-body resection on ventilatory control at rest and during exercise in man. N Engl J Med. 1971;285:1105–1111.
   
3. Gelfand R, Lambertsen CJ. Dynamic respiratory response to abrupt change of inspired CO₂ at normal and high PO₂. J Appl Physiol. 1973;35:903–913.[Free Full Text]
   
4. Berger AJ, Mitchell RA, Severinghaus JW. Regulation of respiration. N Engl J Med. 1977;297:92–97.[Medline] [Order article via Infotrieve]
   
5. Somers VK, Abboud FM. Chemoreflexes: responses, interactions and implications for sleep apnea. Sleep. 1993;16(suppl 8):S30–S34.
   
6. Honig A. Peripheral arterial chemoreceptors and reflex control of sodium and water homeostasis. Am J Physiol. 1989;26:R1282–R1302.
   
7. Fletcher EC, Bao G, Miller CC III. Effect of recurrent episodic hypocapnic, eucapnic, and hypercapnic hypoxia on systemic blood pressure. J Appl Physiol. 1995;78:1516–1521.[Abstract/Free Full Text]
   
8. O'Donnell CP, Schwartz AR, Smith PL, Robotham JL, Fitzgerald RS, Shirahata M. Reflex stimulation of renal sympathetic nerve activity and blood pressure in response to apnea. Am J Respir Crit Care Med. 1996;154:1763–1770.[Abstract]
   
9. Tarasiuk A, Scharf SM. Cardiovascular effects of periodic obstructive and central apneas in dogs. Am J Respir Crit Care Med. 1994;150:83–89.[Abstract]
   
10. Sapru HN. Carotid chemoreflex: neural pathways and transmitters. Adv Exp Med Biol. 1996;410:357–364.[Medline] [Order article via Infotrieve]
    
11. Somers VK, Zavala DC, Mark AL, Abboud FM. Contrasting effects of hypoxia and hypercapnia on ventilation and sympathetic activity in humans. J Appl Physiol. 1989;67:2101–2106.[Abstract/Free Full Text]
    
12. Somers VK, Zvala DC, Mark AL, Abboud FM. Influence of ventilation and hypocapnia on sympathetic nerve responses to hypoxia in normal humans. J Appl Physiol. 1989;67:2095–2100.[Abstract/Free Full Text]
    
13. Daly MD, Angell-James JE, Elsner R. Role of carotid-body chemoreceptors and their reflex interactions in bradycardia and cardiac arrest. Lancet. 1979;1:764–767.[Medline] [Order article via Infotrieve]
    
14. Zwillich C, Devlin T, White D, Douglas N, Weil J, Martin R. Bradycardia during sleep apnea. J Clin Invest. 1982;69:1286–1292.
    
15. Kato H, Menon AS, Slutsky AS. Mechanisms mediating the heart rate response to hypoxemia. Circulation. 1988;77:407–414.[Abstract/Free Full Text]
    
16. Somers VK, Mark AL, Abboud FM. Interaction of baroreceptor and chemoreceptor reflex control of sympathetic nerve activity in normal humans. J Clin Invest. 1991;87:1953–1957.
    
17. Strollo PJ, Rogers RM. Obstructive sleep apnea. N Engl J Med. 1996;334:99–104.[Free Full Text]
    
18. Hedner J, Ejnell H, Sellgren J, Hedner T, Wallin G. Is high and fluctuating muscle nerve sympathetic activity in the sleep apnoea syndrome of pathogenetic importance for the development of hypertension? J Hypertens. 1988;6(suppl 4):S529–S531.
    
19. Carlson JT, Hedner J, Elam M, Ejnell H, Sellgren J, Wallin BG. Augmented resting sympathetic activity in awake patients with obstructive sleep apnea. Chest. 1993;103:1763–1768.[Abstract/Free Full Text]
    
20. Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest. 1995;96:1897–1904.
    
21. Narkiewicz K, van de Borne PJH, Montano N, Dyken ME, Phillips BG, Somers VK. Contribution of tonic chemoreflex activation to sympathetic activity and blood pressure in patients with obstructive sleep apnea. Circulation. 1998;97:943–945.[Abstract/Free Full Text]
    
22. Tafil-Klawe M, Raschke F, Becker H, Hein H, Peter JH. Untersuchungen zur Funktionsdiagnostik der Atmungsregulation bei Patienten mit obstruktivem Schlaf-Apnoe-Syndrom. Pneumonologie. 1989;43:572–575.
    
23. Tafil-Klawe M, Thiele AE, Raschke F, Mayer J, Peter JH, Von Wichert W. Peripheral chemoreceptor reflex in obstructive sleep apnea patients: a relationship between ventilatory response to hypoxia and nocturnal bradycardia during apnea events. Pneumologie. 1991;45:309–311.
    
24. Hedner JA, Wilcox I, Laks L, Grunstein RR, Sullivan CE. A specific and potent pressor effect of hypoxia in patients with sleep apnea. Am Rev Respir Dis. 1992;146:1240–1245.[Medline] [Order article via Infotrieve]
    
25. Vlachogianni ED, Sandhagen B, Gislason T, Stalenheim G. High ventilatory response to hypoxia in hypertensive patients with sleep apnea. Upsala J Med Sci. 1989;94:89–94.[Medline] [Order article via Infotrieve]
    
26. Leuenberger UA, Mawji Z, Waravdekar NV, Zwillich CW. Sympathetic neural responses to transient hypoxia are increased in obstructive sleep apnea. Circulation. 1996;94(suppl I):I-544. Abstract.
    
27. Trzebski A, Tafil M, Zoltowski M, Przybylski J. Increased sensitivity of the arterial chemoreceptor drive in young men with mild hypertension. Cardiovasc Res. 1982;16:163–172.[Medline] [Order article via Infotrieve]
    
28. Burki NK, Baker RW. Ventilatory regulation in eucapnic morbid obesity. Am Rev Respir Dis. 1984;129:538–543.[Medline] [Order article via Infotrieve]
    
29. Kronenberg RS, Drage CW. Attenuation of the ventilatory and heart rate responses to hypoxia and hypercapnia with aging in normal men. J Clin Invest. 1973;52:1812–1819.
    
30. Vgontzas AN, Tan TL, Bixler EO, Martin LF, Shubert D, Kales A. Sleep apnea and sleep disruption in obese patients. Arch Intern Med. 1994;154:1705–1711.[Abstract]
    
31. Victor RG, Leimbach WN Jr, Seals DR, Wallin BG, Mark AL. Effects of the cold pressor test on muscle sympathetic nerve activity in humans. Hypertension. 1987;9:429–436.[Abstract/Free Full Text]
    
32. Wallin G. Intraneural recording and autonomic function in man. In: Banister R, ed. Autonomic Failure. London, UK: Oxford University Press; 1983:36–51.
    
33. Yamamoto K, Iwase S, Mano T. Responses of muscle sympathetic nerve activity and cardiac output to the cold pressor test. Jpn J Physiol. 1992;42:239–252.[Medline] [Order article via Infotrieve]
    
34. Mark AL, Victor RG, Nerhed G, Wallin BG. Microneurographic studies of the mechanisms of sympathetic nerve responses to static exercise in humans. Circ Res. 1985;57:461–469.[Abstract/Free Full Text]
    
35. Anderson EA, Sinkey CA, Lawton WJ, Mark AL. Elevated sympathetic nerve activity in borderline hypertensive humans. Hypertension. 1989;14:177–183.[Abstract/Free Full Text]
    
36. Somers VK, Mark AL, Abboud FM. Potentiation of sympathetic nerve responses to hypoxia in borderline hypertensive subjects. Hypertension. 1988;6:608–612.
    
37. Ziegler MG, Nelesen RA, Mills P, Ancoli-Israel S, Clausen JL, Watkins L, Dimsdale JE. The effect of hypoxia on baroreflexes and pressor sensitivity in sleep apnea and hypertension. Sleep. 1995;18:859–865.[Medline] [Order article via Infotrieve]
    
38. Carlson JT, Hedner JA, Sellgren J, Elam M, Wallin BG. Depressed baroreflex sensitivity in patients with obstructive sleep apnea. Am J Respir Crit Care Med. 1996;154:1490–1496.[Abstract]
    
39. Guilleminault C, Connolly SJ, Winkle RA. Cardiac arrhythmia and conduction disturbances during sleep in 400 patients with sleep apnea syndrome. Am J Cardiol. 1983;52:490–494.[Medline] [Order article via Infotrieve]
    
40. Guilleminault C, Connolly S, Winkle R, Melvin K, Tilkian A. Cyclical variation of the heart rate in sleep apnoea syndrome: mechanisms, and usefulness of 24 h electrocardiography as a screening technique. Lancet. 1984;1:126–131.[Medline] [Order article via Infotrieve]
    
41. Sato F, Nishimura M, Shinano H, Saito H, Miyamoto K, Kawakami Y. Heart rate during obstructive sleep apnea depends on individual hypoxic chemosensitivity of the carotid body. Circulation. 1997;96:274–281.
    
42. Redline S, Tishler PV, Tosteson TD, Williamson J, Kump K, Browner I, Ferrette V, Krejci P. The familial aggregation of obstructive sleep apnea. Am J Respir Crit Care Med. 1995;151:682–687.[Abstract]
    
43. Pillar G, Lavie P. Assessment of the role of inheritance in sleep apnea syndrome. Am J Respir Crit Care Med. 1995;151:688–691.[Abstract]
    
44. Redline S, Leitner J, Arnold J, Tishler PV, Altose MD. Ventilatory-control abnormalities in familial sleep apnea. Am J Respir Crit Care Med. 1997;156:155–162.[Abstract/Free Full Text]
    
45. Kimoff RJ, Brooks D, Horner RL, Kozar LF, Render-Teixeira CL, Champagne V, Mayer P, Phillipson EA. Ventilatory and arousal responses to hypoxia and hypercapnia in a canine model of obstructive sleep apnea. Am J Respir Crit Care Med. 1997;156:886–894.[Abstract/Free Full Text]
    
46. Kimoff RJ, Makino H, Horner RL, Kozar LF, Lue F, Slutsky AS, Phillipson EA. Canine model of obstructive sleep apnea: model description and preliminary application. J Appl Physiol. 1994;76:1810–1817.[Abstract/Free Full Text]
    
47. Brooks D, Horner RL, Kozar LF, Render-Teixeira CL, Phillipson EA. Obstructive sleep apnea as a cause of systemic hypertension: evidence from a canine model. J Clin Invest. 1997;99:106–109.[Medline] [Order article via Infotrieve]
    

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