Clinical Science (1984)66, 665-673
665
Methacholine dose-response curves in normal and asthmatic
man: effect of starting conductance and pharmacological
antagonism
K . F . CHUNG A N D P. D. SNASHALL
Department of Medicine, Grating Cross Hospital Medical School, London
(Received 18 April/30 August 1983; accepted 9 November 1983)
summary
1. The bronchial response of 11 normal and
ten stable asthmatic subjects to increasing concentrations of methacholine aerosol was assessed by
serial measurements of specific airways conductance (scaw) in a body plethysmograph.
2. Cumulative log dose-response curves were
constructed. The threshold provocative dose of
methacholine needed to cause a 35% fall in
starting sCaw (pD35)and the steepest slope of the
response were measured from each curve.
3. On separate days subjects were premedicated with 0.9% NaCl solution (control) in duplicate, chlorpheniramine, salbutamol and atropine,
the last-named at two different doses, one twice
the other.
4. Asthmatic subjects had a lower mean PD35
and a lower mean slope than normal subjects.
5. Pretreatment with salbutamol resulted in a
greater increase in sGaw than after atropine but
caused a smaller increase in PD35 in both groups.
There was a dose-dependent increase in PD3s
after the two doses of atropine, but no significant
difference in bronchodilatation between doses.
Mean steepest slope approximately doubled in
these three sets of challenges.
6. Chlorpheniramine caused a small degree of
bronchodilatation and there was a non-significant
increase in mean PD3s and in mean steepest slope
in both normal and asthmatic groups.
7. There was a positive linear correlation
between starting sGaw and steepest slope in each
group of premedicated challenges, such that when
Correspondence: Dr P. D. Snashall, Department
of Medicine, Charing Cross Hospital Medical
School, Fulham Palace Road, London W6 8RF.
sCaw was high, either spontaneously or due to
bronchodilatation, the slope was steeper.
8. We conclude that increases in PD35 to
methacholine after antagonist drugs are predominantly the result of pharmacological
antagonism. This study has not defined whether
bronchodilatation per se has any effect on PD35.
The steepest slope, being a linear function of
starting sGaw, is a non-specific feature of the log
dose-response curve.
Key words: asthma, atropine, bronchial challenge,
chlorpheniramine, dose-ratio, methacholine, salbutamol.
Introduction
The bronchial response to inhaled bronchoconstrictor agents can be assessed from dose-response
curves which may be analysed in terms of their
slope and position [l]. However, there are considerable difficulties in comparing curves because
their starting airway calibres (as measured, for
instance by FEV,, or airway conductance) are
unlikely to be the same. The problem is particularly severe when trying to assess the antagonistic
activity of drugs which themselves cause bronchodilatation. In order to deal with the problem of
airway calibre many workers [2, 31 have
‘normalized’ their curves by dividing each value by
the starting calibre measurement to give curves
that start from the same value. Others [4-61 use
indices such as the provocative dose to cause a
35% fall in conductance (PDS5)or the provocative
concentration to reduce the FEVl by 20% (PC,),
which imply normalization. This approach may or
may not be valid; it assumes that starting con-
K. F. Chung and P. D. Snashall
666
ductance is a scaling factor for the response and its
slope.
We have previously examined the effect of
spontaneous and drug-induced changes in airway
calibre on the slope of log dose-response curves to
inhaled histamine [7]. The response was measured
as specific airways conductance (sCaw). When
subjects were bronchodilated, the dose-response
curve became steeper in direct proportion to the
increase in starting sGaw. There was, thus, a
positive linear correlation between starting sCaw
and slope, an original finding which tended to
justify the practice of normalization for starting
calibre. An additional finding was that the slopes
of asthmatic subjects were lower in proportion to
their lower starting sCaw, but contrary to the
claims of others [ l ] there did not seem to be any
other influence of asthma on slope.
The purpose of the present study was to confirm and extend these findings by studying
another bronchoconstrictor agent, methacholine, a
long-acting acetylcholine analogue. Control doseresponse curves were compared with those after
premedication with chlorpheniramine, salbutamol
and atropine in a group of normal and asthmatic
subjects.
mitted within 2 h of the start of each experiment.
No subject had a respiratory infection at the time
of the study or during the preceding month.
Experiments were performed at similar times of
the day for each subject, with a minimum of
48 h between successive ones. Each subject was
studied over a period of 3 months.
Measurement
(sCaw)
of specific airway conductance
Airway resistance (Raw) was determined in a
constant-volume body plethysmograph (Fenyves
and Gut, Basel, Switzerland). For each measurement the subject panted at a frequency of 1-2
cycles/s [8], and the thoracic gas volume (TGV)
was measured simultaneously. The output from
the plethysmograph was displayed on an X-Y
plotter and slopes were read by eye. To minimize
variability the curves in a given subject were
always read by the same observer; to minimize bias
the curves were read in batches, without reference
to the experimental circumstances. Specific airways conductance [sGaw = (Raw x TGV)] in
s-l kPa-' was obtained.
Methacholine challenges
Methods
Subjects
Eleven normal and ten stable asthmatic subjects
(Table 1) gave informed consent for the study,
which was approved by the Charing Cross Hospital
Ethical Committee. Two asthmatic subjects were
ex-smokers and three normal subjects were current
smokers. All asthmatic subjects used a salbutamol
inhaler, eight regularly and two occasionally. In
addition, four asthmatic subjects were regularly
using a beclomethasone inhaler and one a sodium
cromoglycate inhaler. Salbutamol was withheld for
at least 8 h before each visit and inhaled steroids
or sodium cromoglycate for at least 24 h. Smoking
and caffeinecontaining beverages were not per-
Methacholine hydrochloride (molecular weight
196), dissolved in 0.9% (w/v) NaCl solution was
delivered intermittently as an aerosol from a
Hudson's nebulizer, which was attached to a
breath-activated 'dosimeter' [4] delivering 8 pl of
aerosol per puff. The nebulizer was triggered by a
fall in mouth pressure at the onset of inspiration.
Subjects were instructed to inspire deeply from
FRC; the duration of nebulization was 0.6 s. The
same nebulizer was used throughout the experiment. Five measurements of resting sCaw were
made over a period of 30 s and then the subject
took five inhalations of 0.9%NaCl aerosol (control
diluent). Two minutes later five more sCaw
measurements were made. The subject then took
five more similar breaths of methacholine solution,
TABLE 1. Characteristics and baseline values of FEVI.o and specific airway conductance (sGaw) of the
normal and asthmatic groups
Values are means f SD.
Subject
Sex
M:F
Age
(years)
Atopic*
Height
(m)
FEV,., (1 BTPS)
Observed
Normal (n = 11)
Asthmatic (n = 10)
5:6
7:3
24.8t4.0
38.6t13.3
4
9
1.71 i0.08
1.71i0.07
Predictedt
3.96i0.55
2.66t0.98
* Positive skin prick tests t o more than four common allergens. t Reference [ 201.
*
Initial sCaw*
(s-l kPa-')
~
3.67i0.58
3.47i0.61
1.89i0.55
0.93k0.43
~________
Measured during fiist visit.
Methacholine dose-response curves
followed by further sGaw measurements. Inhalation of methacholine was repeated at 3 min intervals, the concentration of methacholine being
doubled with each repetition. For normal subjects
these concentrations ranged from 8.0 mmol/l
(1.56 g/l) to 1.02 mol/l (200 g/l). For some
challenges, particularly those after premedication
with antagonist drugs, ten inhalations of 1.02
mol/l solution were used, and occasionally a
further ten inhalations of this concentration. For
asthmatic subjects the starting concentration of
methacholine ranged from 0.25 mmol/l to 2.00
mmol/l. Each challenge was terminated when
sGaw had fallen 50-7076, at which point the
subject was aware of moderate chest tightness and
wheezing. Subjects avoided coughmg and taking
deep breaths, particularly during the phase of
bronchoconstriction. The duration of each methacholine challenge varied between 20 and 35 min.
Two puffs of salbutamol from an inhaler were
given at the end of each challenge and this caused
prompt symptomatic relief.
QP a u
1.2
~4
667
Experimentul pro rocol
Six methacholine challenges were performed on
each subject in order to assess the effect of premedication with antagonists. The fust challenge
was always premedicated with 40 pl of 0.9%NaCl
solution. The remaining five challenges were in
random order and the following drugs delivered
from the Hudson’s nebulizer were used for premedication: (a) 0.9% NaCl solution (five puffs =
40 pl); (b) 0.25% salbutamol sulphate (10 puffs =
0.70 pmol or 200 pg); (c) 0.05%atropine methonitrate (1 5 puffs = 0.164 pmol or 60 pg); (d) 0.05%
atropine methonitrate (30 puffs = 0.328 pmol or
120 pg); (e) 0.5% chlorpheniramine maleate (100
puffs = 10.2 p n o l or 4 mg).
Methacholine challenge was performed 30 min
after premedication. The subjects were not told of
the nature of the premedicating drug.
Methacholine dose-response curves
The arithmetic mean of each set of five sGaw
measurements was plotted against the logarithm
uo
PO uo
Cumulative dose of methacholine bmol)
P.P
.,
FIG. 1. Cumulative log dose-response curves to methacholine in two normal subjects
(open symbols) and two asthmatic subjects (filled-in symbols). Each challenge is
represented according to the prernedicated drug: 0, 0.9% NaCl solution (placebo);
0, 0, chlorpheniramine; 0,+, salbutamol; A, A, atropine (0.164 pmol); v, v, atropine
(0.328 pmol). The three data points to the left of the ordinate indicate respectively
(1) baseline conductance measured when the subject first enters the plethysmograph,
(2) conductance after prernedication, (3) starting conductance measured after
inhalation of diluent.
K. F. Chung and P. D. Snashall
668
to base 10 of the cumulative dose of methacholine
delivered to the subject (Fig. 1). As previously
described [7], we determined from each curve
(a) the starting sGaw measured after inhalation of
diluent, ( b ) the cumulative dose of methacholine
that produced a 35% fall in sGaw (PD,,) and ( c )
the steepest slope of the response.
1S t
2nd
1S t
2nd
r''
Statistical analysis
The starting sCaw values, the PD3, values and
slopes from all challenges were compared by using
a single-factor analysis of variance [9], from which
was derived a least significant difference value that
was used to assess the significance of differences
between the variously premedicated challenges.
P<O.O5 was taken to indicate a statistically
significant difference. For the determination of
the linear relationship between starting sGaw and
slope, and starting sGaw and PDW, the least
squares method was applied and the P value for
the correlation coefficient, r, was obtained from
standard tables [9]. P<O.O5 was chosen as
indicating a significant correlation. In the case of
PD35, a log transformation (to base 10) of (PD35 +
1)pmol was used for all calculations. We have used
geometric mean values for PD35 1 log SD.
*
Results
All subjects completed the study. Tables giving
details of individual dose-response curves (Clinical
Science Table 83/5) are lodged with the Librarian,
The Royal Society of Medicine, London W1M 8AE,
who will supply copies on request.
Lo
PD3,
bmol of methacholine)
Slope
(s-' kPa-' log-' pmol of
methacholine)
FIG. 2. PD35 values and slopes obtained from the
first and second control methacholine challenges
in 11 normal ( 0 ) and ten asthmatic ( 0 ) subjects.
The mean values in each set of challenges are
indicated with vertical bars, representing 1 SEM.
Asthmatic subjects have lower PD3, values and
slopes than normal subjects and there was no
significant difference between these variables for
the first and second control challenges (P> 0.25).
*
sGaw, the coefficient of variation of which was
14% in normals and 36% in asthmatic subjects.
Control methacholine challenges (Fig. 2 )
Inhalation of 0.9% NaCl solution caused a small
but significant reduction in resting sGaw; in
normal subjects mean sGaw fell from 1.89s-'
kPa-'20.55 to 1.84f0.53 (P<0.02) and in
asthmatic subjects from 0.93 f 0.43 to 0.90 f
0.43 (P< 0.05). Mean PD35 was approximately
14-fold lower and mean steepest slope two-fold
less in asthmatic subjects than in normal subjects.
The range of PD35 values was 7.5-fold and 33-fold
in the normal and asthmatic groups respectively;
the corresponding ranges of slope were only threefold and seven-fold. There was an overlap of slopes
but a clear separation of PD, values between
groups. The intrasubject coefficient of variation of
PD35 was 13.8% for normals and 25.8% for
asthmatic subjects; for steepest slope it was 25.1%
and 54.9% respectively. Much of the variability
of slope was accounted for by variations in starting
Effect of salbutamol (Fig. 3 and Fig. 4 )
Mean sGaw increased from 1.90 f 0.56 s-l
kPa-' to 2.67 t 0.86 in normal subjects and from
0.84 f 0.46 to 1.42 f 0.77 in asthmatic subjects.
Salbutamol increased mean PD35 approximately
4.5-fold and seven-fold and mean slope 1.7-fold
and 2.3-fold in normal and asthmatic subjects
respectively.
Effect of atropine (Fig. 3 and Fig. 4 )
(a) After 0.164 pmol of atropine methonitrate
mean sGaw increased from 1.92 f 0.49 to 2.32 f
0.63 in normal subjects and from 0.88 f 0.50 to
1.27 f 0.72 in asthmatic subjects. Mean PD,,
increased approximately nine-fold and 17-fold
and mean slope approximately 1.5-fold and twofold in normal and asthmatic subjects respectively.
Methacholine dose-response curves
669
128
64
4
h
2
32
16
9
B
%
z
P
8
H
3
4
2
1
0.5
0
I
1 .o
2.0
3.0
Starting specific conductance (s-' kPa-')
.. Relationship between mean starting
I
1.o
2.0
3.0
Starting specific conductance (s-l kPa-')
FIG. 3. Relationship between mean starting
specific airway conductance and mean PD35 for
each set of antagonist drugs for asthmatic (filled
symbols) and normal (open symbols) subjects. See
Fig. 1 for definitions of symbols. Each horizontal
and vertical bar indicates f 1 SEM. At comparable
values of mean starting specific conductance,
atropine caused a greater increase in mean PD35
than salbutamol and this increase was dosedependent in both normal and asthmatic subjects.
(b) After the higher dose of atropine (0.328
pmol), mean sGaw in normal subjects increased
from 1.87 f 0.45 to 2.50 f 0.64 and in asthmatic
subjects from 0.94 f 0.45 to 1.50 f 0.69. There
was no significant difference between the starting
sGaw values after salbutamol and atropine at the
two doses used in both groups (P>O.25). PD35
showed an 18-fold and a 37-fold increase from
mean control PD35in normal and asthmatic
subjects respectively. Mean slope increased by
two-fold and 2.5-fold in normal and asthmatic
subjects respectively. The slopes of the salbutamol
and the two atropine-premedicated challenges
were not significantly different for normal subjects (P>O.lO) and for asthmatic subjects (P>
0.25).
Effect of chlorpheniramine (Fig. 3 and Fig. 4)
The first inhalations of chlorpheniramine induced coughing in all normal and asthmatic
subjects, but this ceased as the inhalation pro-
specific airway conductance and mean slope fo;
each set of antagonist drugs for normal and
asthmatic subjects. See Fig. 1 for definitions of
symbols. Salbutamol and atropine (at the two
doses) caused significant increases in mean slopes
in both groups. Chlorpheniramine did not significantly alter mean slope.
ceeded. In normal subjects there was a nonsignificant increase in mean sGaw from 2.03 k 0.67
s-l kpa-'
to 2.09 kO.70 (P>O.l), but in
asthmatic subjects mean sGaw increased signifi:
cantly from 0.78 f 0 . 4 7 to 0.82k0.49 (P<
0.001). On average, an approximately two-fold
and a 1.5-fold increase in PD35was obtained in
normal and asthmatic subjects respectively but
these were not significant (P>O.25). In five
normal and six asthmatic subjects, PD35increased
and, in the remaining subjects, it was unchanged
or it decreased. Steepest slope showed a small,
nonsignificant increase in both normal (P> 0.10)
and asthmatic subjects (P> 0.25).
Starting sGaw and steepest slope
There was a positive linear correlation between
starting sGaw and steepest slope for all challenges
irrespective of premedication. Thus when the
starting sGaw was high either spontaneously or
due to a drug, the slope was steeper (Fig, 4 and
Table 2). The slope of this linear relationship was
approximately 1 except for the control challenges
where it was less than 1 (Table 2). Linear
correlation was also significant for all challenges
for the two groups of subjects combined (Fig. 5).
Within the 21 subjects studied, this relationship
K. F. Chung and P. D. Snashall
670
TABLE2 . Linear regression between starting specific airway conductance and steepest slope f o r each set of
methacholine challenges
Premedicated drugs
0.9%NaCl soh. (control)
Chlorpheniramine
Salbutamol
Atropine (0.164pmol)
Atropine (0.328 pmol)
Normal
n
Regression equation
22
11
11
11
11
y = 0 . 5 4 ~ 0.43
y =0 . 9 9~ 0.32
y = 1 . 2 5 ~- 0.87
y = 0 . 9 5 ~+ 0.07
y = 0 . 9 7 ~ 0.63
+
+
Asthmatic
r
P
n
Regression equation
r
P
0.65
0.88
0.91
0.87
0.71
0,001
<0.001
<0.001
<0.001
<0.02
20
10
10
10
10
y =0 . 7 0~ 0
y = 0 . 8 6 ~- 0.09
0.89
0.93
0.94
0.96
0.95
<0.001
<0.001
<0.001
<0.001
<0.001
= 1 . 1 7 -0.30
~
y = 0 . 9 9 ~- 0.12
y = 1 . 1 7 ~- 0.24
salbutamol-premedicated challenges (n = 10, r =
0.77,P<0.01).
Discussion
Starting specific conductance (s-’ kPa-’)
FIG. 5. Relationship between starting specific
airway conductance and steepest slope of all the
methacholine challenges (66 in 1 1 normal subjects
and 60 in ten asthmatic subjects) and their corresponding steepest slopes. See Fig. 1 for definitions
of symbols. The least squares regression line is
drawn for each group: for normal subjects (- - - )
y=1.13x-O0.45, n = 6 6 , r = 0 . 8 3 , P<O.OOOl
and for asthmatic subjects (-)
y = 0.06~
0.22, n = 60, r = 0.93, P < 0.0001.
was also significant for the six challenges in 15
subjects, with r values ranging from 0.450 to
0.998 (mean r = 0.845).
Starting sGaw and PD35
There was a significant linear correlation
between starting sGaw and PD35in the following
three groups of challenges: (a) in normals: control
challenges (n = 22, r = 0.65, P < 0.002) and
chlorpheniramine-premedicated challenges (n = 1 1 ,
r = 0.76, P < 0.01); ( b ) in asthmatic subjects:
This study with rnethacholine has confirmed and
extended our previous findings with histamine
[7] in the following ways.
(a) There was a positive linear correlation
between starting conductance and the steepest
slope, such that the higher the conductance, the
steeper the slope and vice versa. This relationship
was seen under all circumstances when responses
within subjects and between subjects were compared, with and without prior treatment with
bronchodilator antagonists (Fig. 4). Slopes of the
relationships vary around unity with positive and
negative intercepts (Table 2). Overall, the relationship in asthmatic subjects is flatter and extrapolates more closely to the origin than that in
normal subjects (Fig. 5), which may indicate a
slight curvilinearity of the whole relationship since
a very similar pattern was seen with histamine
challenges [7]. Where asthmatic and normal
conductances overlap, their slopes are in the same
range, suggesting that their dose-response curve
slopes are not fundamentally different and in fact
differ only when starting conductance is different.
Since the regression lines shown in Fig. 5 do
not pass through the origin, ‘normalization’ for
starting conductance is associated with a small
systematic error. Since the regression line in
normals is steeper than in asthmatic subjects the
‘normalized’ slopes will also be slightly steeper.
These findings are relevant to the measurement of
PD35. The use of PD35 assumes that starting conductance is a scaling factor for the slope of the
response, and we have largely justified this assumption, but small errors are inherent in the approach
particularly when normal and asthmatic subjects
are compared.
(b) In conformity with this relationship,
asthmatic subjects with lower starting sGaw values
had lower slopes than normal subjects. Asthmatic
Methacholine dose-response curves
67 1
responsiveness. Studies in a guinea-pig tracheal
chain preparation support this suggestion (K. F.
Chung, T. P. Sloan & P. D. Snashall, unpublished
study).
Quantification of antagonist activity
I
0.01 0.02
0.1 0.2
1.0 2.0 10.0 20.0
Cumulative dose of methacholine bmol)
100
FIG. 6. Effect of normalization on the slopes of
dose-response curves to methacholine from one
normal subject. This subject’s responses are shown
in Fig. 1. The differences in slope seen in Fig. 1
largely disappear when the values for specific
conductance are normalized for the starting value
(1001, not shown). Symbols are as defined in
Fig. 1.
subjects were better distinguished from normal
subjects by their lower PD35values. In this respect,
methacholine was better than histamine. There
was no overlap of PD3, between the two groups
for methacholine and the asthmatic subjects were,
on average, 15 times more responsive to methacholine than the normal subjects; for histamine
the asthmatic hyper-reactivity was only 3.5-fold.
(c) Atropine and salbutamol caused an increase
in starting sGaw and shifted the methacholine
dose-response curve to the right, thereby increasing PD=. When the slopes were adjusted to allow
for the increase in starting sGaw, the shift due to
both antagonist drugs was approximately parallel
(Fig. 6). The same dose of atropine caused a
greater shift in the asthmatic than in the normal
subject.
Relationship between starting conductance and
steepest slope
We believe that the dependence of slope on
starting conductance is due to a basic property of
bronchial smooth muscle. Maximal bronchoconstriction will produce a minimum value for airway conductance close to the abscissa of the
dose-response curve. When a response starts from
a low conductance there is less distance to fall
towards the minimum conductance value than
when starting from a higher value. The slopes
differ because the same increment of dose is
required to go from the point at which the
bronchial response begins, to the point at which
maximum response is obtained regardless of the
starting conductance or the state of bronchial
Since we have observed approximately parallel
shifts of the methacholine dose-response curve
after the three antagonist drugs used, it is
reasonable to use the degree of parallel shift to
quantify the potency of these drugs in vivo. This
can be measured by the single parameter of the
‘dose ratio’ (i.e. PDS5in the presence of antagonist/
control PDB5)as has been described for measuring
the potency in vitro of antagonist drugs on
isolated smooth muscle preparations [lo].
In both groups, salbutamol and atropine
produced similar degrees of bronchodilatation but
salbutamol was a less effective blocker of methacholine-induced bronchoconstriction (Fig. 3).
Atropine was also much more effective in blocking
the effect of methacholine than that of histamine.
In our previous study with histamine [7] we found
that 12.3 pmol of inhaled atropine methonitrate
produced a dose ratio of 4 in normal and
asthmatic subjects, whereas in this study the dose
ratios to methacholine after a 75-fold smaller dose
of atropine were 9 in normal subjects and 18 in
asthmatic subjects. Thus atropine was two orders
of magnitude less effective against histamine than
against methacholine, which casts doubt on the
role of the vagus in histamine-induced bronchospasm [ 111.
Some asthmatic subjects had dose ratios to
atropine outside the range seen in normals at both
doses of inhaled atropine (Fig. 7). According to
the generally accepted equation of competitive
antagonism [12, 131, dose ratio = ([A]/K) 1,
where [A] is the concentration of antagonist and K
is the dissociation constant of the antagonistreceptor complex. Thus, our finding of a h@er
dose ratio in some asthmatic subjects may be the
result either of a greater concentration of atropine
being achieved at the acetylcholine receptor site
in the asthmatic for the same dose of inhaled
atropine, or an increased binding affmity of
atropine to the cholinergic receptor of the
asthmatic airway.
An increased concentration of atropine at the
muscarinic receptor in the asthmatic airway could
result from increased epithelial permeability [141.
In addition, the more central deposition of
inhaled aerosols in the asthmatic subjects [15]
may result in a hgher concentration of atropine at
receptor sites in the large, proximal airways. The
greatest protective effect of atropine was seen in
+
K. F. Chungand P. D. Snashll
612
In conclusion, the methacholine dose-response
curve behaves in a similar way t o the histamine
curve. Our analysis provides a useful method of
comparing the protective effect of antagonist
drugs in the intact human airway. Although our
data suggest that the parallel shifts in PD35 are
the result of pharmacological antagonism, the
exact influence of changes in airway calibre on
shifts in PD35needs further clarification.
160
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Acknowledgments
v
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We are grateful t o the North-West Thames Regional
Health Authority for financial support.
B
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4c
A
A
A
A
v
V
V
V
v
V
"
i
i
n
N
A
N
A
0.164pmol of
0.328pmol of
atropine
atropine
FIG. 7. Individual dose ratios (PDBJafter atropine/
control PD35) in normal (N, open symbols) and
asthmatic subjects (A, filled-in symbols) at the two
doses of atropine. Four asthmatic subjects at the
low dose and five at the high dose have dose ratios
outside the range seen in normal subjects.
the asthmatic subjects who were most hyperresponsive to methacholine, suggesting that the
same factors control reactivity to both methacholine and atropine.
Effect of chlorpheniramine
The lack of any major bronchodilator effect of
inhaled chlorpheniramine is in contrast with our
own previous results [7] and with those of Popa
[16] and Woenne and colleagues [17]. We cannot
adequately explain this discrepancy as the same
preparation of chlorpheniramine was used and was
delivered via the same nebulizer system in both of
our experiments. This variability in response to
chlorpheniramine has also been observed in the
study of Eiser and colleagues [18].Overall, chlorpheniramine did not cause any significant shift of
the methacholine dose-response curve, thus
confirming that it has an insignificant anticholinergic effect in most subjects [17-191.
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Charpin, J. (1977) Airway response to carbachol in
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