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Department of Medicine, Division of Respiratory and Environmental Medicine, Louisville Veterans Affairs Medical Center and University of Louisville School of Medicine, Louisville, Kentucky 40292
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Bao, Gang, Preet M. Randhawa, and Eugene C. Fletcher.
Acute blood pressure elevation during repetitive hypocapnic and eucapnic hypoxia in rats. J. Appl.
Physiol. 82(4): 1071-1078, 1997.
Using a rat
model, we investigated whether episodic eucapnic hypoxia was a more
potent stimulus to acute blood pressure (BP) elevation and bradycardia
than episodic hypocapnic hypoxia. We also investigated the
role of sympathetic and parasympathetic nervous system in this
cardiovascular response. Sprague-Dawley (SD) and Wistar Kyoto (WKY)
rats were exposed to repetitive 30-s cycles of hypocapnic or eucapnic
hypoxia before and after intravenous injection of the
1-adrenergic blocker prazosin,
2-adrenergic blocker yohimbine,
or atropine. Eucapnic hypoxia caused a threefold elevation in systolic
BP from baseline (83.5 ± 3.5 mmHg in WKY, 70.6 ± 4.6 mmHg in
SD) and greater bradycardia (
178 ± 20 beats/min in WKY,
178 ± 21 beats/min in SD) compared with hypocapnic hypoxia (29.8 ± 3.6 mmHg and 43 ± 15 beats/min in WKY,
19.0 ± 4.1 mmHg and 45 ± 12 beats/min in SD). After
prazosin, the BP increase from eucapnic hypoxia was blunted, yohimbine
showed no effect, and atropine blocked the bradycardia. Direct
measurement of sympathetic nerve activity confirmed that adding
CO2 to the hypoxic gas mixture caused a 61% increase in sympathetic nerve activity. WKY rats seem
more vulnerable than SD rats to both hypoxia exposures in terms of the
elevation in BP. We conclude that, in the rat, eucapnic hypoxia is a
more potent stimulus to acute BP elevation and bradycardia than is
hypocapnic hypoxia. An increased sympathetic tone appears to be
involved in the BP response to acute episodic hypoxia.
apnea; sleep apnea syndromes; hypoxemia; sympathetic nervous
system; bradycardia
INTRODUCTION IN PREVIOUS STUDIES using a rat model to simulate
episodic blood oxygen desaturation seen in sleep apnea of humans,
repetitive episodic hypoxia for 35 days induced a significant increase
in diurnal blood pressure (BP) (8). Both carotid body denervation and
sympathetic chemodenervation with the neurotoxin 6-OH-dopamine protected the animals from chronic diurnal BP elevation (6, 7). Because
CO2 retention occurs to some
degree with hypoxemia in apnea of humans (20), we felt that data
regarding the role of CO2 in the
elevation of BP and bradycardia were needed in this model. This study
examines the role of acute episodic hypocapnic hypoxia vs. episodic
eucapnic hypoxia in BP elevation as well as the roles of the
sympathetic and parasympathetic nervous system in the cardiovascular
responses in this model. The reason for development of this model is
the association between acute BP elevation and sleep apnea in humans
(3) and other mammals, as well as the need to study the long term
effects of episodic hypoxia on systemic hypertension (1, 2, 5,
20).
METHODS Male Wistar Kyoto (WKY) and Sprague-Dawley (SD) rats (300-350 g,
Harlan Sprague-Dawley, Indianapolis, IN) were housed in individual cages with daily light from 6:00 AM to 6:00 PM, a standard diet, and
water ad libitum. One day before the experiment, the animals were
anesthetized by intraperitoneal injection of an anesthetic solution
(0.7 ml/kg) consisting of ketamine (42.8 mg/ml), xylazine (8.6 mg/ml),
and acepromazine (1.4 mg/ml). Silastic catheters (0.05-mm ID, Dow
Corning, Midland, MI) were inserted into the femoral artery and
advanced to the abdominal aorta for recording of systemic BP and heart
rate (HR) (12). A similar catheter placed in the inferior vena cava via
the femoral vein was used to infuse pharmacological agents. The
catheters were exteriorized at the nape of the neck.
A previously described method (18) was used to measure sympathetic
nerve activity (SNA). After cannulation of the femoral artery and vein
as described above, the left splanchnic nerve, including the celiac
ganglion, the renal hilum, and adrenal gland, was exposed
retroperitoneally via a flank incision. With the use of microscopic
guidance, the nerve branch between the celiac ganglion and the
suprarenal plexus was carefully separated from fat and connective
tissue over a length of ~8-10 mm. A thin bipolar platinum electrode was placed around a branch of the splanchnic nerve. The
tension between the wires and the nerve was adjusted, and the signals
were controlled via an oscilloscope and audio monitor until the best
signals were received. The electrode and the nerve branch were then
embedded in two-component silicone rubber (Wacker SilGel 604, Germany)
that served to isolate the electrode from surrounding tissues. The
insulated wires of the electrode were fixed with a suture onto the
lumbar muscles, and the end was exteriorized at the neck with a
miniature connector. The flank incision was then sutured, and the
animals were taken back to their cages for a 2-day recovery period.
Before the experiment, the functioning of the electrode was checked by
intravenous injection of 1 µg norepinephrine or 5 µg sodium
nitroprusside. Only rats with SNA signals that responded to the pressor
or depressor effects of the drugs were used for further
experiments.
On the day of experiment, the rats were housed in cylindrical Plexiglas
chambers (2.4-liter volume) with snugly fitting lids (8). The catheters
were connected to Statham P23 DB pressure transducers (Gould, Oxnard,
CA) with bite-proof tubing. The signals were amplified and recorded on
a polygraph (Hewlett-Packard 7858B system, Hewlett-Packard, Waltham,
MA). With the use of a timed solenoid valve,
N2 and
CO2 were infused separately or
combined into the chamber for 12 s, reducing inspired oxygen fraction
(FIO2) and raising inspired
CO2 fraction
(FICO2) to desired concentrations. This was immediately followed by infusion of compressed air, allowing gradual return (over 15-18 s) of gas fractions to ambient levels. Each cycle lasted ~30 s. Before data were recorded, the conscious, unrestrained rats were allowed to acclimatize in chambers for 30 min. The
FIO2 and
FICO2 were measured with a
MiniOX I oxygen analyzer (Catalyst Research, Owings Mills, MD) and a
medical gas analyzer LB2 (SensorMedics, Anaheim, CA), respectively. The
protocol was reviewed and approved by the Institutional Animal Care and
Use Committee at the University of Louisville.
Fig. 1.
Experiment design. A: 6 Sprague-Dawley
(SD) rats were subjected to exposures on day
1 and day 3.
B: cross-section study on day 1 and day
3 in Wistar Kyoto (WKY1,
n = 4; WKY2,
n = 4) and SD (SD1,
n = 4; SD2,
n = 3) rats. Eucap. H., eucapnic
hypoxia; FIO2, inspired
fraction of O2;
FICO2, inspired fraction of
CO2.
[View Larger Version of this Image (21K GIF file)]
1- and
2-adrenoceptors.
Rats (WKY, n = 8; SD,
n = 7) were randomly allocated to one
of four groups (WKY1,
SD1,
WKY2,
SD2) for a 3-day protocol; each rat
served as its own control. Animals were subjected to repetitive hypocapnic (FIO2 3.5%) and
eucapnic hypoxia (FIO2 3.5%, FICO2 10%). On
day 1, immediately after measurement of the responses to five eucapnic hypoxia episodes, groups
WKY1 and
SD1 received an intravenous bolus
injection of the 1-adrenoceptor antagonist prazosin (1 mg/kg, Sigma Chemical, St. Louis, MO), and the
same parameters were measured (Fig.
1B). Groups
WKY2 and SD2 were given intravenous bolus
injection of the 2-adrenoceptor antagonist yohimbine (1 mg/kg, Sigma Chemical), and the same recordings were conducted (Fig. 1B). On
day 3, the same procedure was
repeated, but the injection of prazosin and yohimbine was switched so
that the groups injected with prazosin on day
1 were given yohimbine and vice versa. Because
statistical analysis of the baseline parameters did not reveal any
differences between day 1 and
day 3, data from day
1 and day 3 were
pooled for further analysis.
RESULTS
BP varied inversely with FIO2 and directly with FICO2 (Figs. 2 and 3). The peak change in BP was 14.2 ± 2.2 mmHg above baseline at FIO2 = 10%, reaching 47.5 ± 4.5 mmHg at FIO2 = 1.1% (Fig. 3A). Holding hypoxia at FIO2 = 3.5% while raising the FICO2 to 10% induced greater increases in BP than hypoxia alone (Fig. 3B). Peak BP increased from 27.5 ± 4.8 mmHg at 0% FICO2 to 74.2 ± 6.2 mmHg at 10% FICO2 (nadir FIO2 3.5% constant).
Strain variations. Baseline BP and HR were 118.9 ± 3.7 mmHg and 361 ± 17 beats/min in WKY compared with 116 ± 4.1 mmHg and 375 ± 12 beats/min in SD rats, respectively (not significant). Both strains responded to hypocapnic or eucapnic hypoxia with an increase in BP and bradycardia (Fig. 4). However, WKY rats showed a more profound BP response to both hypocapnic hypoxia and eucapnic hypoxia (29.8 ± 3.6 mmHg in WKY vs. 19.0 ± 4.1 mmHg in SD; 83.5 ± 3.5 mmHg in WKY vs. 70.6 ± 4.6 mmHg in SD, respectively). Whereas bradycardia in both strains was similar during hypocapnic hypoxia (
43 ± 15 beats/min in WKY; 45 ± 12 beats/min in
SD) and during eucapnic hypoxia (178 ± 20 beats/min in WKY,
178 ± 21 beats/min in SD), the response of BP to eucapnic
hypoxia was about threefold higher than the response to hypocapnic
hypoxia.
Sympathetic blockade. After blockade of the
1-adrenoceptors with prazosin,
the increase in BP from eucapnic hypoxia was blunted in WKY as well as
in SD rats, whereas the change in HR was unaffected (Fig.
5). The change in BP was diminished from
86.7 ± 2.8 to 23.3 ± 5.7 mmHg in WKY and from 70.8 ± 5.0 to
33.5 ± 5.3 mmHg in SD rats. In contrast to prazosin, blockade of
2-adrenoceptors with yohimbine did not influence the elevation in BP induced by eucapnic hypoxia (Fig.
6) in WKY or SD rats. Bradycardia was
slightly exaggerated after use of yohimbine in SD rats.
Parasympathetic blockade. In six SD rats, bolus intravenous injection of atropine almost totally abolished bradycardia without affecting the change in BP (Fig. 7).
SNA recording. A typical tracing of BP and SNA is shown in Fig. 8. Insufflating compressed air into the chambers caused little change in BP, HR, and SNA (Fig. 8A). The basal systolic BP was 126 ± 4.8 mmHg, HR (not shown) was 426 ± 21 beats/min, and the peak change in SNA was +3% above baseline. At a nadir FIO2 at 15%, systolic BP increased by 9.0 ± 3.2 mmHg above baseline, HR dropped by
14 ± 9 beats/min, and SNA increased by 28 ± 10%. Further decrease in nadir FIO2
to 13 and 10% caused elevation in BP by 12.4 ± 7.0 and 18.0 ± 4.6 mmHg, respectively; an increase in SNA of 32 ± 9 and 44 ± 10%, respectively; and a decrease in HR by 22 ± 7 and 37 ± 11 beats/min, respectively. Keeping the
FIO2 at 10%
and adding 5% FICO2
exaggerated the elevation in BP (33.2 ± 12.6 mmHg) and bradycardia
(72 ± 18 beats/min). A greater increase in SNA (61 ± 24% above baseline) was also observed. The results from all animals
are summarized in Fig. 9.
Blood-gas analysis. Blood-gas analysis from samples drawn before and during exposure to hypocapnic and eucapnic hypoxia showed progressive changes in PaCO2 and PaO2 above baseline (Table 1). A lower PaO2 was observed during eucapnic hypoxia compared with hypocapnic hypoxia, even though the FIO2 remained the same. There was no difference between the two strains of rats in relation to blood-gas changes.
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DISCUSSION
The new findings of this study are
1) compared with hypocapnic hypoxia,
adding CO2 to the hypoxic gases
causes a larger increase in BP and SNA as well as a bigger drop in HR;
2)
1-adrenoceptors are involved in
the increase in BP; and 3) the
bradycardia occurring with eucapnic hypoxia appears to be vagally
mediated.
Many investigators (10, 19, 20) have emphasized the importance of hypoxia in the pathogenesis of acute periodic hypertension in sleep apnea, whereas the role of CO2 has received less attention (13, 15, 19, 22, 24). Because the magnitude of BP elevation is directly proportional to the severity of oxygen desaturation in sleep apnea patients (20), it is suggested that hypoxemia plays a key role in this process. One reason that the effect of episodic hypoxia, but not its synergistic effect with CO2, has been studied in humans is that, in sleep apnea patients, the absolute change of PaCO2 during sleep is found to be minimal (19), whereas hypoxemia is often impressive. In the present study, the fact that eucapnic hypoxia caused a more than threefold increase in BP compared with hypocapnic hypoxia indicates that CO2 may be important in causing acute changes in BP and HR during episodic hypoxia.
Sympathetic role. The way in which hypoxia and CO2 affect BP is probably multifactorial. Stimulation of chemoreceptors by hypoxia and CO2 may increase sympathetic traffic, affecting BP and HR. In anesthetized dogs, either oxygen desaturation or hypercapnia causes an increase in BP and hindlimb arterial pressure (17). The fact that pharmacological blockade of1-adrenoceptors by prazosin
greatly abolished the periodic elevation in BP is consistent with
investigations showing increased SNA in obstructive sleep apnea (OSA)
patients during apnea (9) as well as in healthy volunteers exposed to
hypoxia (22) or asphyxia (14). The SNA recording in this study further confirmed that the sympathetic nervous system plays an important role
in the BP response to acute episodic hypoxia. Although a further
lowering of FIO2 or increase
in FICO2 might induce even
greater SNA, the SNA measurement in our study was methodologically
limited by the movement of conscious and unrestrained animals exposed
to a lower FIO2 or higher FICO2. Such movement made
the recording of signals very difficult. Evidence toward SNA in apnea
was seen in two OSA patients with Shy-Drager syndrome, an autonomic
insufficiency (19). The lack of an increase in BP in these subjects
indicates that an intact sympathetic reflex pathway is critical in
mediating BP responses. It seems to be clear that an increase in acute
SNA is the final common pathway for apnea-related acute BP elevation. The fact that prazosin blocked the acute periodic hypertension but
yohimbine did not suggests that
1-adrenoceptors
are the major receptors responsible for this effect.
It should be mentioned that after blockade of the
1-adrenoceptors there was still
a small increase in BP. Although prazosin is considered to be a potent
1-adrenoceptor-selective
blocker, the possibility that an incomplete blockade existed may
account for the remaining increase in BP. Another explanation could be that, in addition to sympathetic impulses, other changes induced by
eucapnic hypoxia, such as local or hormonal vasoconstrictors or
vasodilators (endothelin, thromboxane
A2, platelet-activating factor,
nitric oxide, prostacyclin, etc.), were involved in the responses as
well.
Mechanism of bradycardia.
We cannot precisely describe the role of baroreceptor- vs.
chemoreceptor-induced bradycardia. It is possible that the
bradycardia induced by eucapnic hypoxia was baroreflex mediated, a
physiological response to elevation of BP. However, because the
attenuation of the BP elevation after sympathetic blockade did not
affect the bradycardia, it is more likely that a direct stimulation of chemoreceptors was responsible for the drop of HR observed in our
study. Hypoxemia results in bradycardia in anesthetized dogs (4, 11),
implying that chemoreceptors may be responsible for bradycardia. The
fact that in this study atropine eliminated the bradycardia but did not
cause rebound increase in BP, as well as results from other studies in
OSA patients (23) and anesthetized dogs (11), supports the hypothesis
that the bradycardia is vagally mediated. However, it is
speculated that bradycardia may be cardioprotective by limiting the
oxygen requirement of the myocardium and conserving oxygen stores
during apnea (20).
A recent publication supports many of the findings of the present study
regarding the relationship of acute hypoxia, hypercarbia, and SNA.
O'Donnell et al. (16) examined renal SNA in anesthetized cats during
and after central apnea with acute hypoxia. Renal SNA and BP tracked
(increased) oxyhemoglobin desaturation and the responses
were markedly attenuated with the addition of 100% oxygen
to the circuit. Renal SNA was attenuated during the first postapneic
expiration, whereas both renal SNA and BP fell off by the second and
third postapneic breaths. Recording of the distal end of carotid sinus
nerve (carotid chemoreceptor) activity showed a precipitous fall
between the first and second breaths postapnea. The falloff in renal
SNA was attributed to release of baroreceptor inhibition from the
overriding control imposed by the active chemoreceptors that were
beginning to receive reoxygenated blood by the end of the first breath.
These authors also recognized a lesser yet independent effect of
hypercarbia in increasing renal SNA, agreeing with our findings of
increased splanchnic SNA under eucapnic vs. hypocapnic conditions.
These authors concluded that "hypoxic chemoreceptor stimulation was
the predominant factor generating the renal SNA response to apnea, with
modulating inputs from thoracic afferents and arterial baroreceptors
likely contributing to the marked inhibition of renal SNA after
apnea" (16).
Difference in blood-gas changes.
The addition of 10% CO2 to the
gas mixture to create eucapnic hypoxia lowered alveolar oxygen tension,
which in turn caused a lower PaO2 than
hypocapnic hypoxia at the same
FIO2 (Table 1). One
implication of a lower PaO2 could be
that the observed greater increase in BP and bradycardia during
eucapnic hypoxia was caused by the lower
PaO2 rather than by the addition of
CO2. To clarify this concern, an
additional experiment was conducted in five SD rats. As shown in Table
2, the same
PaO2 was achieved by using 3.5%
FIO2 without
CO2 vs. 10%
FIO2 with a 10%
FICO2
(PaO2 43.6 and 46.7 Torr,
respectively; not significant). The corresponding change
in BP was still significantly greater in eucapnic hypoxia. Thus, most
of the increase in BP or bradycardia during eucapnic hypoxia cannot be
explained by a slightly lower PaO2.
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1-adrenergic receptors as
sympathetic receptors mediating this response, probably channeled
through the peripheral chemoreceptors. How this adrenergic-receptor activity is translated into heightened sympathetic activity and chronic
BP changes is yet unknown. Furthermore, this study suggests that the
role of the bradycardia response in this setting does not appear to be
protective in preventing the acute BP rise, because ablation of the
bradycardia by atropine did not accentuate the hypertensive response.
Finally, finding of a strain difference of the rats
response to hypoxia and asphyxia is important because it implies that
genetics may play a role in the sympathetic response. This
may help to explain why only 30-50% of patients
with significant sleep apnea develop systemic hypertension but the
remainder do not. Much work remains to be done to determine the link
between acute and chronic sympathetic activity in response to the
blood-gas changes of apnea.
ACKNOWLEDGEMENTS
This work was supported by the General Research Service of the Department of Veterans Affairs.
FOOTNOTES
Address for reprint requests: G. Bao, Div. of Respiratory and Environmental Medicine, Univ. of Louisville School of Medicine, Ambulatory Care Bldg., Rm. A3L01, 530 South Jackson St., Louisville, KY 40292.
Received 12 September 1996; accepted in final form 19 November 1996.
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K. A. Fagan Physiological and Genomic Consequences of Intermittent Hypoxia: Selected Contribution: Pulmonary hypertension in mice following intermittent hypoxia J Appl Physiol, June 1, 2001; 90(6): 2502 - 2507. [Abstract] [Full Text] [PDF]
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E. C. Fletcher Physiological and Genomic Consequences of Intermittent Hypoxia: Invited Review: Physiological consequences of intermittent hypoxia: systemic blood pressure J Appl Physiol, April 1, 2001; 90(4): 1600 - 1605. [Abstract] [Full Text] [PDF]
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H. Kraiczi, J. Magga, X. Y. Sun, H. Ruskoaho, X. Zhao, and J. Hedner Hypoxic pressor response, cardiac size, and natriuretic peptides are modified by long-term intermittent hypoxia J Appl Physiol, December 1, 1999; 87(6): 2025 - 2031. [Abstract] [Full Text] [PDF]
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BP, mmHg