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-blockade in humans
University Laboratory of Physiology, University of Oxford, Oxford OX1 3PT, United Kingdom
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study
investigated whether changing sympathetic activity, acting via
-receptors, might induce the progressive ventilatory changes
observed in response to prolonged hypoxia. The responses of 10 human
subjects to four 8-h protocols were compared:
1) isocapnic hypoxia (end-tidal
PO2 = 50 Torr) plus
80-mg doses of oral propranolol; 2)
isocapnic hypoxia, as in protocol 1,
with oral placebo; 3) air breathing
with propranolol; and 4) air
breathing with placebo. Exposures were conducted in a chamber designed
to maintain end-tidal gases constant by computer control. Ventilation (
E) was measured at regular intervals
throughout. Additionally, the subjects' ventilatory hypoxic
sensitivity and their residual E during
hyperoxia (5 min) were assessed at 0, 4, and 8 h by using a dynamic
end-tidal forcing technique. -Blockade did not significantly alter
either the rise in E seen during 8 h of isocapnic hypoxia or the changes observed in the acute hypoxic ventilatory response and residual E in
hyperoxia over that period. The results do not provide evidence that
changes in sympathetic activity acting via -receptors play a role in
the mediation of ventilatory changes observed during 8 h of isocapnic hypoxia.
ventilation; hypoxic sensitivity; high-altitude acclimatization
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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VENTILATORY ACCLIMATIZATION to hypoxia involves a slow
and progressive rise in ventilation (E),
which in turn produces a slow increase in end-tidal
PO2
(PETO2), a slow decrease in
end-tidal PCO2
(PETCO2), and a progressive respiratory alkalosis. These changes start within the first few hours
of the acclimatization process, and during this time the rise in
E is accompanied by an increase in the
peripheral chemoreflex sensitivity to acute hypoxia [acute
hypoxic ventilatory response (AHVR)]. At the cessation of the
hypoxic exposure, and return to either euoxic or hyperoxic conditions,
E does not immediately revert to normal
but remains somewhat elevated. The mechanisms that underlie these early
stages of acclimatization are not fully understood, but it has been
established that the main stimulus pathway does not involve the fall in
PCO2 and rise in pH that normally
accompany hypoxia. During isocapnic hypoxia, the progressive increase
in E is actually more pronounced than during poikilocapnic hypoxia (2, 19), presumably because of the absence
of a hypocapnic braking effect. Both the increase in AHVR and the
increase in E under conditions of acute
hyperoxia (compared with prehypoxic values) do not depend on whether
the exposure was isocapnic and poikilocapnic (18, 36).
One possible mechanism is that changes in autonomic function underlie
part of the slow respiratory adaptation to hypoxia. This notion is
supported by the observation that circulating and urinary
norepinephrine levels increase progressively in humans during exposure
to high altitude (11, 25, 26), and this increase has been shown to
correlate with an increase in E (1). Although increases in circulating levels of norepinephrine can increase
both E and, more specifically, AHVR (10),
there is also substantive evidence that carotid body function may be
modulated directly by its own sympathetic supply. This evidence
includes the observation that electrical stimulation of the sympathetic input to the carotid body (the preganglionic sympathetic trunk) in the
anesthetized cat can increase chemosensory discharge (29). Both the
human respiratory response to increases in circulating norepinephrine
and the carotid body response to stimulation by norepinephrine in
experimental animals may be blocked by -blockade (15, 16).
Given these observations, the hypothesis we wished to test in the
present study was whether increases in -receptor-mediated sympathetic activity underlie the respiratory changes that occur early
in the ventilatory acclimatization to hypoxia. We studied the response
to hypoxia alone by maintainence of
PETCO2 at the subject's
normal air-breathing level. In particular, we studied three different
aspects of the ventilatory response. First, we studied the effect of
the drug on the progressive increase in E
seen during sustained hypoxia. Second, we investigated whether the
elevation in E that remains
during brief periods of hyperoxia imposed within the overall hypoxic
exposure could be altered by the drug. Third, we examined whether the
increase in AHVR observed during prolonged hypoxia was affected by the drug.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects. We studied 10 subjects [6 men, 4 women; ages, 23.2 ± 3.3 (SD) yr; height, 181.3 ± 8.4 cm; weight, 72.1 ± 8.4 kg]. None of the subjects had a history of respiratory or cardiovascular disease. All subjects gave informed consent to the study. The study had been approved by the Central Oxford Research Ethics Committee.
Protocols.
The protocols were designed to allow us to compare the effects of
hypoxia with and without -blockade. Air-breathing protocols with and
without the drug served as control exposures. Overall, the volunteers
were subjected to four protocols on four different days (in varied
order, with protocols separated by at least 1 wk). Female subjects were
only studied during the first 2 wk of their menstrual cycles, unless
they were taking a contraceptive pill, because levels of circulating
progesterone are known to affect aspects of ventilation, such as
CO2 sensitivity (12, 13).
-blocker (propranolol) were given every 8 h, starting 16 h before
the experiment began (protocol
IH-P). 2)
Isocapnic hypoxia, as in protocol
IH-P, except that, in this protocol, placebo tablets were given in place of propranolol at the same times as in
protocol IH-P
(protocol IH-C).
3) Air-breathing control, in which
propranolol was given as in protocol
IH-P (protocol C-P).
4) Air-breathing control, in which
placebo was given as in protocol IH-C
(protocol C-C).
E was measured during these protocols
at intervals of 0, 1, 2, 4, 6, and 8 h after the start. At 0, 4, and 8 h, the subjects' AHVR and E were
determined under conditions of acute hyperoxia. The
PETO2 profile used for these
measurements is shown in Fig. 1. A 5-min
lead-in period at a PETO2 of
100 Torr was followed by six square waves, with
PETO2 alternating between 50 and 100 Torr and with each gas level being maintained for 1 min. After
the last step, the PETO2 was
increased to 300 Torr and was maintained at that level for 5 min.
PETCO2 was kept at 1-2
Torr above the subject's normal air-breathing value for the duration
of these measurements.
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Experimental technique. For the main 8-h hypoxic and control exposures, individual subjects were seated inside a clear-sided experimental chamber, where they could pursue activities such as watching television or reading. Inside this chamber, the ambient PO2 and PCO2 could be altered. The subjects wore a nasal cannula, held in place with a nasal O2-therapy mask, and PETO2 and PETCO2 together with inspired PO2 and PCO2 were measured by using a mass spectrometer (Airspec QP9000, Biggin Hill, UK). Before the start of the exposures, each subject's normal PETCO2 value was determined during a 5-min period of air breathing. During the exposure, the subjects also wore a pulse oximeter (Ohmeda Biox 3740, Louisville, KY) that served as a safety device. At the start of the experiment, the desired end-tidal gas values were entered manually into a controlling computer that regulated the gas composition inside the chamber. Every 5 min, the computer compared the average end-tidal gas values of the previous 3 min with the desired values, and the chamber gas composition was adjusted, if necessary, to keep end-tidal values constant. The chamber and its control system have been described in more detail elsewhere (17).
Measurements ofE in the chamber were
undertaken by using a respiratory inductance plethysmograph (Studley
Data Systems, Oxford, UK). For each determination of
E, a 5-min measurement period was
followed by a 5-min calibration period. During the measurement period,
data were collected from the inductance plethysmograph with no
disturbance of the subject. During the calibration period, subjects
breathed via a mouthpiece and noseclip arrangement through a turbine
volume-measurement device (SensorMedics VMM series, CardioKinetics,
Salford, UK) while data continued to be collected by using inductance
plethysmography. The signals obtained from inductance plethysmography
in the second period of 5 min could thus be calibrated by using the
simultaneous measurements of respiratory volumes, and the calibration
coefficients so obtained were then used to calibrate the data obtained
in the first 5 min without the use of the mouthpiece and noseclip.
The responses to square waves of hypoxia to assess AHVR and to short
periods of hyperoxia were measured outside the chamber by using a
mouthpiece and noseclip arrangement. Respiratory volumes were sensed
with a turbine volume-measurement device. Respiratory flows and timing
information were recorded with a Fleisch pneumotachograph. Gas was
sampled continuously from a port close to the mouth, and inspired
PO2 and
PCO2 together with
PETO2 and
PETCO2 were measured by
using a mass spectrometer (Airspec MGA3000). The subject was also
connected to an electrocardiograph (Rigel cardiac monitor 302, Morden,
UK) to monitor heart rate and wore a pulse-oximeter probe (Ohmeda Biox
3740) on one finger as a safety device to monitor saturation. A
computer recorded the respiratory variables every 20 ms, logged the
occurrence of each QRS complex from the electrocardiogram, and
determined the values for
PETO2 and
PETCO2.
Gas control was achieved by using a computer-controlled fast gas-mixing
system (20). The required inspiratory gas composition was derived from
a combination of a prediction of values from a model of the
cardiorespiratory system and a breath-by-breath correction of the
deviation of the actual values from the measured values. This
prediction-correction scheme has been described in more detail
elsewhere (32).
Model fitting.
Numerical values for AHVR were obtained by fitting a model of the
ventilatory response to acute hypoxia to the data obtained during the
square waves of hypoxia. The particular model employed was
model 3 of Clement and Robbins (9). In
this model, total E has been
represented as the sum of ventilation at 100% saturation (c), which
has generally been ascribed to the central chemoreflex, and a
ventilation which has been ascribed to the peripheral chemoreflex (p). In the
present experiments, PETCO2
was maintained constant; therefore,
c may be
considered constant. Under conditions of both steady
PETCO2 and steady
PETO2,
p would be
equal to Gp (1 
S),
where the gain term Gp is the
hypoxic sensitivity at the fixed
PETCO2, representing the
slope of the increase in E with a
decrease in saturation (S). Therefore, under these conditions,
E=
c + Gp (1 S). However,
under the conditions of dynamic hypoxic stimulation that we have been studying, it is also necessary to take into account the time constant (
) that represents the time E takes
to move toward a new steady-state value when the saturation is changed,
and the time delay
(td) that
represents the time it takes blood with a given saturation in the lungs
to reach the carotid bodies, where the stimulus acts to produce the
ventilatory response. The differential equation for this model is
![&tgr; <FR><NU>d<A><AC>V</AC><AC>˙</AC></A><SC>e</SC></NU><DE>d<IT>t</IT></DE></FR> + <A><AC>V</AC><AC>˙</AC></A><SC>e</SC> = <A><AC>V</AC><AC>˙</AC></A><SUB>c</SUB> + <IT>G</IT><SUB>p</SUB> [1 − <IT>S</IT>(<IT>t</IT> − <IT>t</IT><SUB>d</SUB>)]](/content/vol86/issue6/fulltext/1897/img001.gif)
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td) remains
constant from the beginning to the end of individual breaths, the
equation may be solved to yield E for
breath i, as a function of the input
(S), the parameters of the model, and the value of
E for breath
i 1.
![(<A><AC>V</AC><AC>˙</AC></A><SC>e</SC>)<SUB><IT>i</IT></SUB> = {<A><AC>V</AC><AC>˙</AC></A><SUB>c</SUB> + <IT>G</IT><SUB>p</SUB> [1 − S(<IT>t</IT> − <IT>t</IT><SUB>d</SUB>)]}](/content/vol86/issue6/fulltext/1897/img002.gif)
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![− {<A><AC>V</AC><AC>˙</AC></A><SUB>c</SUB> + <IT>G</IT><SUB>p</SUB> [1 − <IT>S</IT>(<IT>t</IT> − <IT>t</IT><SUB>d</SUB>)] − (<A><AC>V</AC><AC>˙</AC></A><SC>e</SC>)<SUB><IT>i</IT>−1</SUB>} ⋅ <IT>e</IT><SUP>−(<IT>t</IT><SUB>1</SUB>−<IT>t</IT><SUB>i−1</SUB>)/&tgr;</SUP>](/content/vol86/issue6/fulltext/1897/img003.gif)
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c,
Gp, , and
td. These
parameters were estimated by nonlinear regression by using the Numerical Algorithms Group (Oxford, UK) Fortran library routine E04FDF
to minimize the sum of squares of the residuals. S was calculated from
the measured PETO2 values by
using the hemoglobin dissociation function as described by Severinghaus (35).
Statistical analysis.
The main variables of interest were the values for
E in hypoxia or euoxia in
the chamber (averages over the last 4 min of the 5-min measurement
period were used), the values for E in hyperoxia (averages over the last 3 min of the 5-min measurement period
were used), and the values for Gp
and c from the
model fitting. ANOVA was used to test for significant differences
between the responses to the four protocols. The particular factor of interest in the ANOVA was the interaction between drug, hypoxia, and
time, because this addresses the question of whether the drug significantly altered, over time, the response of the respective variables to hypoxia.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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All 10 subjects completed the study successfully, although some suffered from headaches during the second half of the hypoxic exposures.
Effectiveness of -blockade.
Table 1 shows the heart rate response at
various time points for the four protocols. It can be seen that
-blockade of the heart was effective, as heart rate was always
substantially lower than in the placebo protocols (ANOVA,
P < 0.001).
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End-tidal gas values before and during protocols.
Values for air-breathing
PETCO2 at the beginning of
the experimental day were slightly but significantly
(P < 0.05) lower in the presence of
propranolol than when placebo had been taken (means ± SD of 5-min
averages of breath-by-breath end-tidal values: propranolol protocols,
37.7 ± 4.5 Torr; placebo protocols, 39.1 ± 4.0 Torr). Figure
2, B and
C, shows the gas control obtained in
the chamber for the four protocols. Average values of
PETO2 (excluding
t = 0) were 52.5 ± 0.8 Torr in
protocol IH-P, 52.3 ± 0.6 Torr in
protocol IH-C, 108.7 ± 5.9 Torr in
protocol C-P, and 109.1 ± 3.1 Torr
in protocol C-C. Average values of
PETCO2 were 37.5 ± 4.0 Torr (0.2 ± 0.8 Torr difference from target value) in
protocol IH-P, 38.9 ± 3.7 Torr
(0.2 ± 0.3 Torr difference from target value) in
protocol IH-C, 37.8 ± 4.8 Torr in
protocol C-P, and 38.8 ± 3.3 Torr
in protocol C-C.
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E during hypoxia.
Figure 2A shows the ventilatory
response to the four protocols, as measured by inductance
plethysmography in the chamber. Interestingly, no initial effect of
hypoxia on E was apparent in these
subjects, although this may simply be the result of rather high values
for E at
t = 0 in the chamber (compare
t = 0 values with the remainder for
the euoxic protocols). Nevertheless, E did increase with time during the hypoxic exposures (circles) but not
during the air control experiments (squares). However, there was no
significant difference between the response in the presence of
propranolol (closed symbols) and in the presence of placebo
(open symbols), during either the hypoxic exposure or the air control.
E during acute hyperoxia.
Table 2 shows the mean
E responses to the hyperoxic
exposure during the last 3 min of the test. These values are somewhat higher than those observed under hypoxic conditions within the chamber.
In part, this reflects the fact that the hyperoxic data were obtained
at a somewhat higher PETCO2
than the hyperoxic data were, but it may also be related to the
different techniques used to determine
E under the two conditions
(inductance plethysmography in hypoxia and turbine flowmeter with
mouthpiece and noseclip in hyperoxia). It can be see that in both
hypoxic protocols, E was elevated at 4 and 8 h (ANOVA, hypoxia by time, P < 0.001). On inspection of the data, there appeared to be a difference in general baseline between the four protocols. This was confirmed by
ANOVA (hypoxia by drug, P < 0.05).
However, there was no significant effect for the interaction between
drug, hypoxia, and time, i.e., the drug did not affect the response
over time to hypoxia.
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E during square waves of hypoxia.
Figure 3 shows a typical breath-by-breath
individual response to the square waves of hypoxia used to assess AHVR
and the subsequent period of hyperoxia. In this figure, a vigorous
ventilatory response to hypoxia is shown, together with the good
control over PETO2 and
PETCO2 that was achieved by
using the end-tidal forcing system. Figure
4 shows the average of the first five (in
some cases 4) square waves averaged for all 10 subjects at
t = 0, 4, and 8 h for the four
protocols. It is evident from this figure that, in both hypoxic
protocols, both E overall and the
amplitude of the response to acute hypoxia were increased. Table
3 shows the corresponding values of
Gp,
c, , and
td obtained from
the model for each protocol.
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c represents
E at 100% saturation. As such, it is
notable that the calculated parameter from the model follows the same pattern as E measured during
hyperoxia, as described above. Just as in the case of the measured
hyperventilation during hyperoxia, c significantly
increased over time during the hypoxic exposure (ANOVA, hypoxia by
time, P < 0.001), and there was a
baseline difference between the protocols (ANOVA, hypoxia by drug,
P < 0.05). Again, however, the drug
did not significantly affect the response of
c to hypoxia
over time.
Sustained hypoxia significantly increased the time constant () which
indicates the time taken for E to reach a
new steady-state level after the hypoxic step (ANOVA, hypoxia by time,
P < 0.05), but propranolol had no
significant effect on this parameter. Conversely, hypoxia significantly
decreased the time delay (td) (ANOVA, hypoxia by
time, P < 0.05), and propranolol
seemed to have the effect of increasing
td during both hypoxia and
air control (ANOVA, P < 0.001)
without abolishing the decrease seen during hypoxia.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The main finding of this study was that the early stages of the human
ventilatory acclimatization to isocapnic hypoxia could not
significantly be altered by -adrenergic blockade with propranolol. In particular, the following features associated with an 8-h exposure to isocapnic hypoxia (PETO2 = 50 Torr) were all unaffected by the drug:
1) the progressive increase in
E, 2)
the persistent hyperventilation observed during short spells of
hyperoxia, and 3) the increase in AHVR
observed during short periods in which PETO2 was varied acutely.
Methodological considerations.
Propranolol is a lipid-soluble, nonspecific, -adrenergic-receptor
blocker capable of crossing the blood-brain barrier. Any effects seen
could, therefore, have been brought about through peripheral or central
mechanisms that act at 1- or
2-receptors. The dose of
propranolol used in this study was the same as that used in various
studies of cardiorespiratory responses at altitude (1, 21, 26-28).
Bodem et al. (3) found that heart rate in humans was maximally blocked
at an oral dose of propranolol of 200 mg/day, subdivided into doses
given at 6-h intervals. This observation, coupled with the depression
of heart rate that was observed in the present study (Table 1),
suggests that the dose of propranolol employed was adequate for
effective -blockade.
Isocapnic vs. poikilocapnic hypoxia.
The exposure to hypoxia that was employed in this study was isocapnic,
and the question arises, To what extent are the findings likely to be
applicable to hypoxic exposures in which the
PETCO2 is allowed to fall
naturally, such as during travel to high altitude? As outlined in the
introduction, the increases in both AHVR and residual
E under conditions of acute hyperoxia
have been found to be similar, whether or not the hypoxic exposure was
maintained isocapnic (18, 36). Thus the influence (or lack thereof) of -blockade is unlikely to be affected by the type of hypoxic exposure employed. More recent experiments have also found no difference between
isocapnic and poikilocapnic exposures, even in the case of exposures
lasting for 48 h (14, 37). These findings have also demonstrated that
the increase in E under conditions of acute hyperoxia arises through an increase in ventilatory sensitivity to CO2.
Comparison with other studies in humans.
We are unaware of any studies directly comparable with the one
presented in this paper, in which the focus has been on the early
changes in the ventilatory acclimatization to isocapnic hypoxia and in
which an attempt has been made to separate out different components of
the respiratory response (AHVR, hyperoxic E) which may be mediated by different
mechanisms. Two studies have investigated ventilatory changes with and
without -blockade during prolonged exposures to high altitude, i.e.,
during prolonged poikilocapnic hypoxia. Moore et al. (27) examined the
ventilatory response of men to 15 days' residence at Pikes Peak (4,300 m) with and without -blockade (80 mg propranolol given every 8 h). Although there were differences in metabolic rate between the two
groups, the progressive fall in
PETCO2 over time between the
groups was similar; this suggests that -blockade did not affect the
process of ventilatory acclimatization to hypoxia. Asano et al. (1)
also studied men on Pikes Peak, this time for 21 days with or without
the same dose of propranolol as used by Moore et al. In the study by
Asano et al., E was not altered by the
drug, but the ventilatory changes were related to urinary levels of
norepinephrine. Therefore, these researchers suggested that there is a
close link between ventilatory and sympathetic activation during
hypoxia, but that this linkage is brought about by a non--adrenergic mechanism.
-blockade on
the acute response to hypoxia at t = 0. This is in keeping with most other studies of the effect of
-blockade on the acute ventilatory response to hypoxia (4, 16, 22,
30). Only one study was able to demonstrate a significant depression of E with -blockade (100 mg bupranolol),
during both air breathing and hypoxia (8). The authors suggested that
E increased less during hypoxia
when the subjects received the -blocker, although this effect
appears to have been small.
Other possible mechanisms related to autonomic activity.
There are various other ways in which the autonomic nervous system
could modulate ventilatory control during hypoxia that are not
dependent on -adrenergic mechanisms. These include 
-adrenergic mechanisms, central mechanisms independent of - or -receptors, and parasympathetic mechanisms.
-adrenergic mechanisms, in the cat there is evidence
that 2-receptors are present in
the carotid body and that they exert inhibitory influences (23).
Furthermore, the inhibitory effect associated with intracarotid
infusions of an 2-receptor
agonist on the carotid body appeared to be attenuated or lost after the
animal had undergone a 24- to 36-h exposure to hypoxia before the
infusion (6). This suggests that there may be a downregulation of the
2-adrenergic inhibitory
mechanism during the ventilatory acclimatization to hypoxia. However,
other studies in other species were unable to confirm this finding
(33). Moreover, O'Regan (29) was unable to abolish the increase in chemoreceptor discharge in response to sympathetic stimulation of the
chemosensory cells with either an - or a -adrenergic blocker.
In relation to possible central mechanisms, adrenergic mechanisms are
unlikely to play a role, because norepinephrine and epinephrine have
been shown to exert a central depressant action on respiration (7). In
the rat, however, it has been shown that chemoreceptor activation
stimulates neurons in the rostral ventrolateral medulla, and that these
neurons, in turn, innervate and activate preganglionic sympathetic
neurons of the spinal chord (31); this demonstrates that there are
central links between the peripheral chemoreceptors and the sympathetic
nervous system.
It is unlikely that slow changes in the parasympathetic input to the
carotid body cause slow increases in
E during prolonged hypoxia,
because parasympathetic efferents have an inhibitory influence on
carotid body discharge (34, 38), and this inhibition may be increased
after prolonged exposure to hypoxia (24).
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ACKNOWLEDGEMENTS |
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We thank D. F. O'Connor for skilled technical assistance.
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FOOTNOTES |
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This work was funded by the Wellcome Trust. C. Clar held a Biotechnology and Biological Sciences Research Council Research Studentship.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests: P. A. Robbins, Univ. Laboratory of Physiology, Univ. of Oxford, Parks Rd., Oxford OX1 3PT, UK (E-mail: peter.robbins{at}physiol.ox.ac.uk).
Received 29 July 1998; accepted in final form 1 February 1999.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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,
Isocapnic hypoxia + propranolol; 
, isocapnic hypoxia + placebo; 
,
air control plus propranolol; and 
, air control + placebo. Gas
control for PETO2
(B) and
PETCO2
(C) at the times when
