From the Cardiovascular Division, Department of Internal Medicine (K.N.,
P.J.H.v.d.B., V.K.S.), Department of Neurology (M.E.D.), and Division of
Clinical and Administrative Pharmacy (B.G.P.), University of Iowa, Iowa City,
and Centro Ricerche Cardiovascolari, CNR, Medicina Interna II, Ospedale L.
Sacco, Università 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
Methods and Results—Using a double-blind, randomized,
vehicle-controlled design, we examined the effects of chemoreflex
deactivation (by comparing effects of breathing 100% oxygen for 15
minutes with effects of breathing room air for 15 minutes) on MSNA,
heart rate, blood pressure, and minute ventilation in 14 untreated
patients with OSA and in 12 normal subjects matched for age and body
mass index. All control subjects underwent overnight polysomnography to
exclude the existence of occult OSA. Baseline MSNA was markedly
elevated in the patients with OSA compared with the control subjects
(44±4 versus 30±3 bursts per minute; P=.01). In both
control subjects and patients with OSA, heart rate decreased during
administration of 100% oxygen but did not change during administration
of room air. By contrast, both MSNA (P=.008) and mean
arterial pressure (P=.02) were significantly
reduced during chemoreflex deactivation by 100% oxygen only in
patients with OSA but not in control subjects.
Conclusions—Tonic activation of excitatory chemoreflex afferents
may contribute to increased efferent sympathetic activity to muscle
circulation in patients with OSA.
Peripheral arterial chemoreceptors have a
significant physiological activity in normoxia, the
so-called "resting drive."3 4 5 In normal
subjects, chemoreflex deactivation with 100% oxygen may cause a
reduction in MSNA.6 We therefore hypothesized
that tonic chemoreflex activation might contribute to the increased
sympathetic outflow even during normoxic wakefulness in patients with
OSA and that chemoreflex deactivation with 100% oxygen would therefore
cause a reduction in sympathetic nerve traffic and a decrease of blood
pressure in these patients. Using a double-blind, randomized,
placebo-controlled design, we examined the effects of chemoreflex
deactivation on sympathetic activity and blood pressure in patients
with OSA and normal subjects matched for age and BMI.
We also studied 12 healthy control subjects (9 men) matched for age and
BMI (mean age, 43±3 years; mean BMI, 32±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
Protocol and Procedures
Analyses
Demographic data and baseline characteristics during breathing of room
air were compared by use of an unpaired t test. The
responses to administration of 100% oxygen and room air were assessed
as comparisons between measurements taken during the last 5 minutes of
baseline with measurements averaged over 15 minutes of hyperoxia or
room air administration. Data were analyzed by
repeated-measures ANOVA with time (before versus during gas
administration) as within factor and gas (100% oxygen versus room air)
as between factor. The P values for differences within a
session were obtained by post hoc tests (planned contrasts). The key
variable was the gas-by-time interaction. Data are
presented as mean±SEM. A value of P<.05 was
considered significant.
Ventilatory responses to 100% oxygen were not significantly different
from those observed during room air in both control subjects and
patients with OSA (Table 2
In patients with OSA, chemoreflex deactivation decreased MSNA
(P=.008) and MAP (P=.02)
(Figure
Studies in animals indicate that tonic chemoreflex activation even
during normoxia has significant effects on both blood pressure and
heart rate, probably mediated by sympathetic
activation.9 Previous studies in humans show that
100% oxygen elicits reductions in MSNA and not blood pressure, but in
normal-weight young subjects.6 Another possible
explanation for the previously observed decrease in MSNA during 100%
oxygen in normal subjects might be acclimation to the laboratory
setting and to mouthpiece breathing. In the present study, 100%
oxygen decreased MSNA and MAP in both normal obese control subjects and
patients with OSA. However, the changes in MSNA and MAP during
administration of 100% oxygen were significantly different from those
during room air administration only in patients with OSA, because room
air breathing was also accompanied by a tendency toward a fall in MAP
and MSNA in the obese control subjects in our study. This underscores
the importance of the double-blind, vehicle-controlled study
design.
The fall in MSNA and heart rate elicited by 100% oxygen was evident
even though baseline oxygen saturation was normal in patients with
sleep apnea and was accompanied by a fall in blood pressure. This
suggests a causal interaction between the reductions in MSNA, heart
rate, and blood pressure, because reductions in blood pressure would
otherwise elicit increases in MSNA and heart rate. We also confirm
previous findings of higher MSNA in patients with sleep
apnea.1 2 Norepinephrine may be an
important contributor to increased chemoreceptor
drive.9 10 We speculate that the chronic high
levels of efferent sympathetic activity in patients with OSA may be
implicated in the high tonic arterial chemoreceptor
drive.
In conclusion, chemoreflex deactivation decreases MSNA and blood
pressure in patients with OSA but not in normal obese subjects without
sleep-related disordered breathing. Thus, tonic chemoreflex activation
may contribute to increased sympathetic activity and blood pressure in
patients with OSA.
Received December 18, 1997;
accepted January 6, 1998.
2.
Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic
neural mechanisms in obstructive sleep apnea. J Clin
Invest. 1995;96:1897–1904.
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Binet L, Dejours P. Le role des chemorecepteurs
arteriels dans la controle de la respiration pulmonaire chez l'homme.
Arch Int Pharmacodyn. 1962;139:328–335.
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Menschen vom O2-Druck abhängige Erregungen
der Chemoreceptoren eine Rolle? Pflugers Arch. 1953;257:349–362.[Medline]
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Honig A. Peripheral arterial
chemoreceptors and reflex control of sodium and water homeostasis.
Am J Physiol. 1989;26:R1282–R1302.
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Seals DR, Johnson DG, Fregosi RF. Hyperoxia lowers
sympathetic activity at rest but not during exercise in humans.
Am J Physiol. 1991;260:R873–R878.
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Wallin G. Intraneural recording and autonomic
function in man. In: Banister R, ed. Autonomic Failure.
London, UK: Oxford University Press; 1983:36–51.
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Schobel HP, Fischer T, Heuszer K, Geiger H, Schmieder
RE. Preeclampsia: a state of sympathetic overactivity. N
Engl J Med. 1996;335:1480–1485.
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Przybylski J, Trzebski A, Czyzewski T, Jodkowski J.
Responses to hyperoxia, hypoxia, hypercapnia and almitrine in
spontaneously hypertensive rats. Bull Eur Physiopathol
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Milsom WK, Sadig T. Interaction between
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© 1998 American Heart Association, Inc.
Brief Rapid Communications
Contribution of Tonic Chemoreflex Activation to Sympathetic Activity and Blood Pressure in Patients With Obstructive Sleep Apnea
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Muscle sympathetic nerve
activity (MSNA) is increased in patients with obstructive sleep apnea
(OSA). We tested the hypothesis that tonic activation of excitatory
chemoreceptor afferents contributes to the elevated sympathetic
activity in OSA.
Key Words: nervous system, autonomic • nervous system, sympathetic • apnea, sleep • blood pressure • heart rate
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Patients with
obstructive sleep apnea (OSA) have high levels of muscle sympathetic
nerve activity (MSNA).1 2 Because of obstructive
apneas during sleep, these patients are exposed to repetitive episodes
of hypoxia, hypercapnia, and apnea, all of which result in
chemoreflex activation and consequent MSNA increase during
sleep.2 However, sympathetic activity is also
increased during the daytime in these patients, even in awake, normoxic
conditions.1 2 The mechanisms underlying the
chronically increased sympathetic activation in patients with OSA are
not known.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Subjects
We studied 14 patients (11 men) with newly diagnosed OSA (mean
age, 44±3 years; mean BMI, 32±1 kg/m2) who were
normotensive, were free of any other diseases, were on no medications,
and had never been treated for sleep apnea. All sleep apnea patients
were also free of any history, symptoms, or signs suggestive of
congestive heart failure. The severity of sleep apnea was defined on
the basis of the apnea-hypopnea index, indicating the number of
respiratory irregularities per sleep hour. Mean apnea-hypopnea index
for the 14 sleep apneic patients was 39±6 events per hour.
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 partial
pressure was monitored with a Hewlett-Packard 47210A Capnometer. Minute
ventilation was determined with an S430 ventilation measuring system
(KL Engineering) that uses a precision, ultralight, unidirectional,
inertia-compensated, turbine flow transducer. Breathing was via a
mouthpiece with a nose clip to ensure exclusive mouth breathing.
Sympathetic nerve activity to muscle was recorded as described
previously.7
Subjects were studied in the supine position. To study the
effect of chemoreflex deactivation with 100% oxygen, we used a
randomized, double-blind, placebo-controlled crossover design. Placebo
consisted of breathing room air. Baseline measurements before
administration of 100% oxygen or room air were taken during a
10-minute period while the subject was breathing room air through a
mouthpiece. One hundred percent oxygen or room air was then
administered via a mouthpiece for 15 minutes. After a 30-minute
recovery, the identical protocol (10 minutes of baseline followed by a
double-blinded administration of either 100% oxygen or room air for 15
minutes) was repeated.
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. Measurements of
nerve activity at baseline before each gas administration (100% oxygen
or room air) were expressed as 100%. Sympathetic activity was also
expressed as bursts per minute, which allows comparison of sympathetic
discharge between individuals,2 8 thus permitting
a comparison of resting MSNA between sleep apnea patients and control
subjects. Measurements were made by a single observer (K.N.) blinded to
subject and intervention.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Baseline characteristics of the patients with OSA and control
subjects during breathing of room air are shown in Table 1
. Oxygen saturation, end-tidal
CO2 partial pressure, MAP, and heart rate in
patients with sleep apnea were not significantly different from those
observed in obese subjects without sleep apnea. Baseline MSNA was
markedly elevated in the patients with OSA compared with the control
subjects (44±4 versus 30±3 bursts per minute; P=.01).
View this table:
[in a new window]
Table 1. Baseline Measurements of Patients With OSA and
Normal Control Subjects ). In both
control subjects and patients with OSA, heart rate decreased during
100% oxygen but did not change during room air (Table 2).
View this table:
[in a new window]
Table 2. Effects of 100% Oxygen and Room Air in Normal
Subjects and in Patients With Sleep Apnea , Table 2
). By contrast, the
effects of 100% oxygen and room air on MSNA and MAP in control
subjects were not different (Table 2). The changes in MSNA during 100%
oxygen administration in patients with OSA did not correlate with the
baseline oxygen saturation levels (r=.31;
P=.27).
View larger version (30K):
[in a new window]
Figure 1. Recordings of MSNA in a single patient with OSA
during administration of 100% oxygen (top) and room air (bottom).
MSNA, MAP, and heart rate (HR) decreased during administration of 100%
oxygen but did not change during administration of room air.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
This double-blind, randomized, vehicle-controlled study indicates
that chemoreflex deactivation with hyperoxia decreases MSNA and blood
pressure in normoxic, normotensive patients with OSA but not in normal,
obese control subjects. Thus, elevated sympathetic nerve activity to
muscle in patients with OSA might be explained in part by tonic
activation of excitatory chemoreflex afferents.
Selected Abbreviations and Acronyms
BMI
=
body mass index
MAP
=
mean arterial pressure
MSNA
=
muscle sympathetic nerve activity
OSA
=
obstructive sleep apnea
Acknowledgments
Dr Narkiewicz, a visiting 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 Grant-in-Aid, NIH grant
HL-14388, and an NIH Sleep Academic Award (Dr Somers). We thank Diane
Davison, RN, MA, for technical assistance.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
1.
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.
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S. HEINDL, M. LEHNERT, C.-P. CRIEE, G. HASENFUSS, and S. ANDREAS Marked Sympathetic Activation in Patients with Chronic Respiratory Failure Am. J. Respir. Crit. Care Med., August 15, 2001; 164(4): 597 - 601. [Abstract] [Full Text] [PDF]
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K. Narkiewicz, M. Kato, B. G. Phillips, C. A. Pesek, D. E. Davison, and V. K. Somers Nocturnal Continuous Positive Airway Pressure Decreases Daytime Sympathetic Traffic in Obstructive Sleep Apnea Circulation, December 7, 1999; 100(23): 2332 - 2335. [Abstract] [Full Text] [PDF]
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K. Narkiewicz, P. J. H. van de Borne, C. A. Pesek, M. E. Dyken, N. Montano, and V. K. Somers Selective Potentiation of Peripheral Chemoreflex Sensitivity in Obstructive Sleep Apnea Circulation, March 9, 1999; 99(9): 1183 - 1189. [Abstract] [Full Text] [PDF]
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