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Institute for Child Health Research, Perth, Western Australia 6001, Australia; and Department of Medical Informatics and Engineering and Institute of Experimental Surgery, Albert Szent-Györgyi Medical University, H-6701 Szeged, Hungary
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Peták, Ferenc, Zoltán Hantos, Ágnes
Adamicza, Tibor Asztalos, and Peter D. Sly. Methacholine-induced
bronchoconstriction in rats: effects of intravenous vs. aerosol
delivery. J. Appl. Physiol. 82(5):
1479-1487, 1997.
To determine the predominant site of action of
methacholine (MCh) on lung mechanics, two groups of open-chest
Sprague-Dawley rats were studied. Five rats were measured during
intravenous infusion of MCh (iv group), with doubling of concentrations
from 1 to 16 µg · kg
1 · min1.
Seven rats were measured after aerosol administration of MCh with doses
doubled from 1 to 16 mg/ml (ae group). Pulmonary input impedance
(ZL) between 0.5 and 21 Hz was
determined by using a wave-tube technique. A model containing airway
resistance (Raw) and inertance (Iaw) and parenchymal damping (G) and
elastance (H) was fitted to the
ZL spectra. In the iv group, MCh
induced dose-dependent increases in Raw [peak response 270 ± 9 (SE) % of the control level; P < 0.05] and in G (340 ± 150%;
P < 0.05), with no increase in
Iaw (30 ± 59%) or
H (111 ± 9%). In the ae group, the
dose-dependent increases in Raw (191 ± 14%;
P < 0.05) and
G (385 ± 35%; P < 0.05) were associated with a significant increase in H (202 ± 8%; P < 0.05).
Measurements with different resident gases [air vs. neon-oxygen
mixture, as suggested (K. R. Lutchen, Z. Hantos, F. Peták,
Á. Adamicza, and B. Suki. J. Appl.
Physiol. 80: 1841-1849, 1996
[Medline]
)] in the
control and constricted states in another group of rats suggested that
the entire increase seen in G during the iv
challenge was due to ventilation inhomogeneity, whereas the ae
challenge might also have involved real tissue contractions via
selective stimulation of the muscarinic receptors.
airway resistance; lung tissue resistance; forced
oscillations
INTRODUCTION PREVIOUS STUDIES on respiratory mechanics at
frequencies above those of spontaneous breathing rate or performed on
isolated airways led to the belief that methacholine (MCh) causes
constriction merely of the conducting airways. Recently, partitioning
of the lung resistance (RL)
into airway (Raw) and parenchymal (Rti) parts has established the
importance of the lung tissues in the pulmonary responsiveness to
various constrictor stimuli (11, 13, 14, 18, 19, 21-27).
Nevertheless, numerous conflicting data have been reported on the site
of action of bronchoactive agonists such as MCh or histamine. In a
number of studies, the pulmonary tissue has been shown to be
responsible for the major increase in the resistive pressure drop
across the lungs after a MCh aerosol challenge (18, 27) or after a
bolus intravenous (iv) infusion (13). Inhalation of MCh was reported to
elevate Raw and Rti to a similar degree in dogs (21). In
contrast, no increase was observed in the parenchymal hysteresis in
humans after a MCh aerosol challenge, whereas the airways seemed to
respond (14, 19). In all of the above studies the airways were
demonstrated to respond to a MCh challenge, but practically no increase
in Raw was detected in rabbits after MCh inhalation, whereas the Rti
and elastance increased eight- and threefold, respectively (22).
Furthermore, Sato et al. (24) found a fairly uniform tissue
constriction, whereas Raw displayed an obvious elevation in two dogs,
only a slight increase in a third, and even a decrease in the fourth.
Recently, Nagase et al. (18) investigated the mechanism that gives rise
to Rti, by inducing constriction with an iv or aerosol administration
of MCh. They demonstrated that aerosolized MCh had a greater effect on
the airways, whereas iv delivery generated higher parenchymal
responses. They argued that the latter phenomenon may be related to a
heterogeneous response of the peripheral airways. More recently, by
provoking smaller increases in Rti, Salerno et al. (23) obtained a
fundamentally different pattern of effect, depending on whether the MCh
was inhaled or iv delivered.
Most of these contradictions can be attributed to methodological
factors. Both in vivo and in vitro studies have suggested that MCh
increases the inhomogeneity of the lung periphery (11, 18), and it has
been pointed out that, in the presence of a peripheral inhomogeneity,
the uncertainties associated with the sampling of alveolar pressure
(PA) with alveolar capsules
may lead to false estimations of airway and tissue responses to
constrictor stimuli (11). It should be also recalled that the vast
majority of the studies referred to above used alveolar capsules to
sample PA. On the other hand, it
has been demonstrated that model parameters derived from low-frequency
pulmonary input impedance data
(ZL) adequately characterize
the airway and lung tissue properties both under control conditions
(8-12, 15, 16, 20, 24, 28) and during pulmonary constriction (11,
12, 15, 17).
It is unclear what portion of the contradictory data relating to the
relative contributions of the airways and parenchyma to MCh-induced
constriction can be attributed to the different routes of MCh delivery.
The purpose of the present study was a systematic exploration of how
the predominant site of action of MCh in the respiratory tract differs,
depending on the route of administration, within a single strain of
rat. To avoid any possible carryover effect, the studies were performed
in two separate groups of rats. In the first group of rats, MCh was
infused iv, whereas the second group was challenged with aerosolized
MCh. Overall airway and lung tissue responses were separated by fitting
a model containing an airway and a parenchymal compartment to
low-frequency ZL data (11).
METHODS Animal Preparation
ZL Measurements
ZL was measured with the wave-tube technique (6, 12, 29). The tracheal cannula was switched from the respirator at end expiration and connected to a loudspeaker-in-box system through a 120-cm length of polyethylene tubing (2-mm inner diameter). Before each measurement, the pressure in the box chambers was adjusted to 2.5 cmH2O to keep the transpulmonary pressure unchanged during measurements. The wave-tube was equipped with sidearms and miniature transducers (ICS model 33NA002D) to measure the lateral pressures at the loudspeaker end (P1) and the cannula end (P2). The loudspeaker was driven by a computer-generated small-amplitude pseudorandom signal containing 23 noninteger-multiple components between 0.5 and 21 Hz and producing a <2-cmH2O peak-to-peak excursion in P1. The signals of P1 and P2 were low-pass filtered (5th-order Butterworth, 25-Hz corner frequency) and digitized at a sampling rate of 128 Hz by an analog-to-digital board of an AT486 IBM-compatible computer. The pressure-transfer functions (i.e., P1/P2) were computed by fast Fourier transformation from the 6-s recordings by using 4-s time windows and 95% overlapping. According to the transmission line theory, ZL can be calculated from the P1/P2 spectra as the load impedance of the wave tube (6, 12, 29)
![Z<SC>l</SC> = Zo sin<IT>h</IT> (&ggr;<SC>l</SC>)/[(P<SUB>1</SUB>/P<SUB>2</SUB>) − cos<IT>h</IT> (&ggr;<SC>l</SC>)]](/content/vol82/issue5/fulltext/1479/img001.gif)
|
are the characteristic impedance and the complex propagation
wave number, respectively, both determined by the geometrical data and
the material constants of the tube and the air (4).
Study Protocol
iv Challenge. MCh was infused at rates of 1, 2, 4, 8, or 16 µg · kg1 · min1.
Before each infusion, the lungs were hyperinflated by occluding the
expiratory outlet of the respirator for one cycle, i.e., producing two
superimposed inspirations. Four successive measurements of ZL, 1 min apart, were made and
the infusion was then started. The duration of each infusion was 10 min, and ZL was measured 30 s
after the onset of the infusion and every 1 min thereafter. The
infusion was suspended for at least 15 min to let the blood pressure
recover before the next series of control and infusion measurements was
begun.
Aerosol challenge.
After four successive baseline measurements, solutions of saline or 1, 2, 4, 8, or 16 mg/kg MCh were delivered for 40 s each by an ultrasonic
nebulizer (model 2000, DeVilbiss) via the inspiratory port of the
respirator. Before each delivery, two inspiratory phases were
superimposed to standardize the volume history. Measurements were
started 30 s after completion of each aerosol challenge, and six
successive recordings were collected during every 30 s. The next dose
was administered 60 s after the last recording.
Parameter Estimation
The ZL data were evaluated in terms of a model containing an airway compartment characterized by frequency-independent resistance (Raw) and inertance (Iaw) and a constant-phase tissue compartment including tissue damping (G) and elastance (H)
|
is the
angular frequency, and exponent 
is expressed as = 2/
arctan
(H/G). Pulmonary hysteresivity (
) (7) was calculated as G/H.
In the iv group, three to five ZL spectra were ensemble averaged in each preinfusion state and at the peak responses. Because of the absence of a plateau response after the MCh aerosol challenge, parameters corresponding to the peak response in Raw were used for analysis in the ae group. The data at frequencies coinciding with the heart rate and its harmonics were often corrupted, as evidenced by poor coherence and a high SD, and they were omitted from the model fitting.
Statistical Analysis
Scatters in the parameters were expressed in SE values. We used one-way analysis of variances with Dunnett's multiple comparison procedure to compare the parameters from the control with those obtained after MCh challenges. Two-way analysis of variances with the Student-Newman-Keuls multiple comparison procedure was applied to compare the effects of iv and aerosolized MCh. Each test was performed with a P < 0.05 significance level.Validation of Airway-Tissue Separation
To validate the airway and tissue parameters derived from model fitting, we measured another group of animals breathing air and then a mixture of 80% neon + 20% oxygen (NeOx) under both control and steady-state constricted conditions, as suggested by Lutchen et al. (15). Three rats were challenged with 16 and 32 µg · kg1 · min1
iv infusions of MCh, and three were challenged with 4 mg/ml aerosolized MCh. To allow for measurements both with air and with NeOx, a stable
level of constriction was required. This was achieved by continuing
each challenge for 30 min.
We used a modified setup to collect
ZL data. The wave tube was not
directly connected to the loudspeaker box. To allow for accurate
control of the gas concentration in the system as well as rapid change
in the composition of the oscillatory gas, a bag-in-box system was
inserted between the loudspeaker and the wave tube. The loudspeaker
oscillated the air in the box, and the opening of the bag was led
transmurally to the wave tube. The material constants of the air or the
NeOx were used to calculate Zo and .
Before the NeOx measurements, four to six data epochs each were collected when the lungs were filled with room air at baseline and when a steady-state constriction was observed. The rats were then switched to breathe NeOx from a reservoir attached to the inspiratory port of the respirator. When the NeOx concentration had equilibrated (~90 breaths), four to six measurements were made with the NeOx-filled bag in the box.
RESULTS
Typical ZL data recorded in the
control state and at three iv MCh-infusion rates are presented in Fig.
1. The low variabilities of the
ZL data indicate very stable
plateau responses in this animal. MCh caused increases in the real part
of ZL (i.e.,
RL) at all frequencies, but
they were more obvious in the low-frequency range; in general, these
elevations were accompanied by minor changes in pulmonary reactance
(XL) in the iv group but by
more marked decreases in XL in
the ae group. Apart from the small systematic fitting error in the two
lowest-frequency points of the real parts during MCh challenge, the
model fits the ZL data well,
with an average fitting error (F) of
2.6 ± 0.1% in the ae group and 2.9 ± 0.1% in the iv group,
respectively. F showed no
statistically significant differences between the control and the
constricted states in either group. There were no statistically
significant differences between the baseline parameter values from the
two groups.
) and
during 2 (
), 4 (
), or 8 (
)
µg · kg1 · min1
intravenous methacholine (MCh) infusions, respectively. Values are
means ± SD; n = average of
3-5 successive measurements under each condition. Lines,
corresponding model fits. Impedance data corrupted by cardiac noise
were omitted from model fit (open symbols).
iv Challenge
Figure 2 summarizes the airway and tissue parameters obtained in the control state and at the different MCh-infusion rates. Similar MCh-induced elevations occurred in Raw, G, and, which reached 270 ± 90%
(P < 0.05), 340 ± 150% (P < 0.05), and 301 ± 102% (P < 0.05), respectively, of
their control values. We observed no significant changes in Iaw or in H
throughout the infusions, although Iaw in one rat displayed a marked
decrease during the highest infusion rate, causing a fall in the
average value. No residual effect of iv MCh was found; every parameter
returned to its baseline value between infusions (data not presented).
) in iv group. C, control. *Significantly different
from control, P < 0.05.
Aerosol Challenge
Changes in the averaged airway and parenchymal parameters for the ae group are shown in Fig. 3 for control and MCh challenges. None of the model parameters exhibited significant changes after saline nebulization. Inhalation of increasing concentrations of MCh caused monotonous and statistically significant elevations in all parameters except Iaw, with the changes beginning after the 2 mg/kg concentration. In response to the highest dose, Iaw was seen to decrease significantly. The group mean values of Raw, Iaw, G, and at peak response were 191 ± 14 (P < 0.05), 73 ± 8 (P < 0.05), 385 ± 35 (P < 0.05), and 190 ± 13%
(P < 0.05), respectively, of the
control levels. In contrast to the iv MCh challenge, monotonic and
statistically significant elevations were found in H, which increased
after the highest dose to 202 ± 8%
(P < 0.05) of the control value.
in aerosol
administration of MCh (ae) group. S, saline. * Significantly different from control, P < 0.05.
Airway and Tissue Responses: Aerosol vs. iv Delivery
To examine further the differences in the predominant site of action of MCh on lung mechanics, depending on the route of delivery, in Fig. 4 we have plotted the model parameters for the iv group against the corresponding values for the ae group, both normalized by the control values. If the pattern of change were the same in response to iv and aerosol challenges, we would expect a linear relationship between the changes in each variable, with the dose equivalence between the two routes of delivery represented by the slope of the relationship. Different slopes for different variables would indicate a difference in the relative dose-response characteristics for the two delivery routes. In fact, our data demonstrate quite different relationships for different variables. A two-way analysis of variance, with the route of challenge as the first and the dose of MCh as the second factor, revealed that iv administration of MCh induced a significantly higher Raw and a lower Iaw than those after the aerosol challenge. The increases in G were significantly higher in response to the inhalation challenge than after the iv challenge of successive doses. The relative changes in H were highly dissociated: statistically significantly greater elevations were found for the last three aerosol doses than for the corresponding iv concentrations. As follows from the different patterns in G and H, the iv MCh increased significantly more than did the corresponding
aerosol dose.
The statistical analysis also revealed that, irrespective of the route
factor (i.e., ae or iv), MCh exerted highly significant effects on all
parameters (P < 0.005). Furthermore,
independently of the dose factor, the changes in Raw, Iaw, and were
not different in the two populations, whereas the relative changes in G
and H in the ae group were significantly greater than those in the iv
group (P < 0.02 and
P < 0.001, respectively).
Model Validation
In both groups of rats involved in the NeOx experiments, when the lungs were filled with air, MCh induced a pattern of change in the model parameters similar to that obtained in the main groups of animals (Figs. 2 and 3), although the exposure of the animals to aerosolized MCh was different from that for the main group of rats (continuous aerosol challenge). For the animals breathing air, Raw increased (63 ± 11%) and Iaw slightly decreased (
11 ± 4%) after the
16 µg · kg1 · min1 MCh infusion. An
increase in G (35 ± 18%) was seen, with practically no
change in H (14 ± 10%). In the rats challenged with 4 mg/ml aerosolized MCh, a moderate increase in Raw (24 ± 18%) and no change in Iaw (9 ± 7%) occurred. The increase in G (125 ± 97%) was accompanied by an increase in H (86 ± 58%).
To evaluate the differences due to the change of the resident gas in
the lungs, we calculated the NeOx-to-air parameter ratios. When a
steady-state NeOx concentration is established in the lungs, the
physical principles would lead to the expectation that
RawNeOx/Rawair reflects the predicted ratio of the viscosities (1.4), whereas IawNeOx/Iawair
reflects that of the densities (0.8) of the two gas mixtures.
Furthermore, as Lutchen et al. (15) argued, the tissue parameters
should be independent of the resident gas in the normal lung. Figure
5 shows these data for the rats
challenged with iv MCh. In the control condition, the ratios for
Raw and Iaw were 1.47 ± 0.04 and 0.75 ± 0.06, respectively. The
estimates of G and H were independent of the resident gas, as shown by
ratios not significantly different from unity (1.0 ± 0.0 and 0.96 ± 0.05 for G and H, respectively). During 16 µg · kg1 · min1
MCh infusion, the ratios of Raw (1.39 ± 0.01) and Iaw (0.76 ± 0.06) were similar to those obtained under control conditions. No
systematic dependence on the intrapulmonary gas was found for H
(1.04 ± 0.09), whereas the ratio of G increased (1.16 ± 0.06). After elevation of the MCh dose to 32 µg · kg1 · min1,
the NeOx-to-air ratios of Raw and H remained unchanged (1.46 ± 0.07 and 1.01 ± 0.02, respectively), whereas that of G increased further
(1.27 ± 0.15) and
IawNeOx/Iawair
decreased (0.49 ± 0.08).
1 · min1
iv MCh infusions in 3 individual rats.
The NeOx-to-air parameter ratios for the control conditions and during
continuous 4 mg/kg aerosolized MCh challenge are shown in Fig.
6. The ratios obtained under control
conditions were very similar to those obtained during MCh infusion. The
ratio of Raw again reflects the difference in the gas viscosities (1.47 ± 0.03), whereas the Iaw ratio shows the effect of the different
densities (0.72 ± 0.05). The estimates of both G (1.02 ± 0.02)
and H (1.03 ± 0.03) were not sensitive to the resident gas in the
lungs. Like the moderate iv challenge, the constriction induced by
aerosolized MCh had no influence on the ratios of Raw (1.53 ± 0.08), Iaw (0.71 ± 0.03), or H (1.06 ± 0.05). However, G again
showed a marked gas dependence (1.21 ± 0.11) during constriction.
DISCUSSION
To examine whether the site of action of MCh differs, depending on the
route of administration, we partitioned the response of the lung into
airway and parenchymal components when the agent was either inhaled or
administered iv. We found significant differences between inhalation
and iv delivery. The iv challenge induced roughly a threefold increase
in Raw and similar elevation in G. No increases in Iaw or H were seen.
The different patterns of change in G and H resulted in marked
elevations in . The aerosol delivery of MCh induced two- and
fourfold increases in Raw and G, respectively. In contrast with the iv
delivery, a twofold, highly significant elevation was also observed in
H. The combination of the patterns in the tissue parameters resulted in
a moderate elevation in .
Model Appropriateness
Our ZL spectra agree qualitatively with those reported on dogs (10-12, 24, 28), cats (8), and rabbits (16) and are very similar to those obtained in rats (9, 15). The ability of the constant-phase model to afford an accurate description of the tissue mechanics and thereby separate the airway and parenchymal components of the total ZL has been demonstrated in different species under control (8, 10-12, 15, 16, 20, 28) and constricted conditions (11, 12, 15, 17). Both in the present study and in previous reports, the model fitted equally well to ZL data obtained after aerosol and iv challenges. Our confidence in the model performance is reinforced by the results of the present model validation studies involving the use of different resident gases. In agreement with the results reported by Lutchen et al. (15), the baseline lung tissue properties were not affected when the intrapulmonary air was replaced by NeOx, and the ratios of Raw and Iaw reflected the viscosity and density ratios, respectively, of the intrapulmonary gases. Accordingly, our data confirm their conclusion, i.e., airway inhomogeneities do not influence the estimates of airway and parenchymal mechanics from low-frequency ZL spectra obtained under control conditions. In addition, during both iv and aerosolized delivery of MCh, the NeOx-to-air ratios of Raw, Iaw, and H remained at the baseline level, whereas G was higher when the lung was filled with NeOx. This finding is also fully consistent with the results of Lutchen et al. (15), confirming that airflow inhomogeneities due to heterogeneous constriction of the peripheral airways can contribute to an increase in G.Predominant Site of Action of MCh
iv Infusion. Our data indicate that MCh delivered by iv infusion has a significant effect on the airway caliber. Furthermore, our dose-response curves permit an insight into the serial distribution of the bronchoconstriction. MCh induced a significant increase in Raw, whereas Iaw remained at the baseline level at doses producing moderate constriction. Because Iaw is thought to be primarily a property of the central airways, it may be concluded that iv MCh induced bronchoconstriction in the peripheral airways. The interpretation of the parenchymal response is not as obvious and requires a short review of the assumptions inherent in the partitioning method. We assume that the asymptotic value of the real part represents the frequency-independent Raw, and the entire frequency dependence of the low-frequency real and imaginary parts can be attributed to the viscoelasticity of the parenchyma. At baseline, our tissue parameters were independent of the resident gas in the lungs, confirming that these assumptions are likely to be valid in healthy lungs (15). The GNeOx/Gair ratio increased from 1.00 at baseline to 1.16 and 1.27 during iv MCh infusion at 16 and 32 µg · kg1 · min1,
respectively. This finding also confirms the observation of Lutchen et
al. (15) that the enhanced airway inhomogeneity induced by severe
constriction can add a significant artifactual (i.e., not of tissue
origin) frequency dependence to the low-frequency real part, and hence
G. Consequently, a MCh-induced elevation in G can either occur as a
result of changed intrinsic tissue damping or originate from peripheral
ventilation inhomogeneity.
After iv administration, we found a significant (4-fold) increase in G,
whereas H remained at the baseline level. This finding is
similar to the results obtained by Lutchen et al. (15) in Wistar rats,
although they observed a slight (12.8%) but statistically significant
elevation in H during the 16 µg · kg1 · min1
MCh infusion, which accompanied a marked (44%) increase in G. They
argued that enhanced airway inhomogeneities increased the frequency
dependence of RL and lung
elastance (EL).
The MCh-induced changes in the parameters obtained in the present study
during iv administration suggest the same phenomenon: the entire
increase in G during iv challenge is likely to be artifactual and can
be attributed solely to inhomogenous airway constriction. Alternatively, it may be assumed that the lack of change in one of the
primary determinants of tissue mechanics (H) was accompanied by
increases in , the other primary tissue parameter (5), and this was
reflected by the elevated values of G (= H). Although our
supplementary measurements with different resident gases (Fig. 5)
substantiate that peripheral airway inhomogeneity was the major contributor to the increase in G (and ), we cannot exclude the possible involvement of an altered tissue hysteresivity.
The notion of pure airway constriction in response to an iv MCh
challenge is somewhat surprising and contradicts all of the previous
studies. In the same rat strain that we used in the present study,
Nagase et al. (18) partitioned airway and lung tissue responses to an
iv MCh challenge. They used alveolar capsules and multilinear
regression analysis of the airway opening pressure, tracheal
airflow, and PA
signals during mechanical ventilation to calculate lung mechanics and
found approximately five- and threefold elevations in Rti and
EL, respectively. Similar results were reported in guinea
pigs by Ingenito et al. (13), who calculated the enclosed area of the
pressure-volume curves seen at the airway opening and in alveolar
capsules. However, when the dose of iv-administered MCh was restricted
to modest levels, Salerno et al. (23) reported a fundamentally
different tissue response in Brown Norway rats. They found that Rti
approximately doubled, whereas the highest increase in
EL was <20%. Similarly, Sato
et al. (24) reported that Rti was doubled after an iv bolus of MCh in
dogs, whereas the increase in EL
was 30-50%. In addition to methodological differences between
those reports and the present study (tidal ventilation vs.
small-amplitude oscillation at functional residual capacity), it should
also be pointed out that we use a frequency-independent elastance
coefficient (H), whereas the EL
values reported above were effective elastances calculated at
respiratory frequencies. Indeed, the
EL values calculated from our
XL data at 1.75 Hz
(a frequency typically applied in rat studies with alveolar capsules) revealed dose-dependent increases in
EL, reaching statistically significant levels during 8 (26 ± 11%,
P < 0.05) and 16 µg · kg1 · min1
(91 ± 58%, P < 0.05) MCh
infusions. As pointed out by Lutchen et al. (15), this discrepancy
between the MCh-induced changes in
EL and H can be attributed to
the phenomenon that peripheral airway inhomogeneities leading to
increases in G may also increase the positive frequency
dependence of the effective
EL, whereas the
intrinsic elastic and resistive properties of the tissues do not
change.
Aerosol challenge.
The aerosol administration of MCh results in a similar pattern of
change in the airway parameters to that observed during iv challenge.
Therefore, the above considerations allow the conclusion that
constriction occurred in the peripheral airways. We additionally found
consistent and significant increases in both G and H, although those in
G were always higher than those in H. Accordingly, consistent and
significant elevations were found in . The elevations in G can
either be explained on the basis of changes in intrinsic tissue
properties (5) or, to some extent, can be attributed to increased
peripheral inhomogeneities (3, 11, 15, 17). The results of our NeOx
experiments during an aerosolized MCh challenge indeed confirm that the
estimation of G is influenced by inhomogeneities. Nevertheless, the
dose-dependent elevations in H suggest that aerosolized MCh induced
constriction in both the airways and the parenchyma. This finding is
fully consistent with previous reports documenting parenchymal
responses to an aerosolized MCh challenge, in which the separation of
airway and tissue properties was accomplished by alveolar capsules (18, 21, 22, 27).
Reasons for Different Patterns With iv and Aerosol Challenge
A possible explanation for the different patterns of response of the lung, depending on the route of delivery, is that MCh acts on different structures when delivered by inhalation or iv. MCh produces a muscle contraction by stimulating the muscarinic cholinergic receptors (2). Sly et al. (25) investigated the role of the muscarinic receptors in puppies and reported that different receptors may be involved in producing airway and parenchymal constriction to inhaled MCh. M3 receptors located on the airway smooth muscle, which are likely to be responsible for airway responses, may be more easily reached by iv-delivered MCh, whereas MCh delivered by aerosol has to diffuse across the respiratory epithelium before reaching the muscle. On the other hand, M1 receptors in the alveolar wall, which were reported to be involved in the parenchymal response (25), are likely to be reached more easily by aerosol delivery than by iv delivery. Under this scenario, it may be expected that an MCh infusion, delivered preferentially to the airway smooth muscle, will produce primarily airway constriction, whereas aerosolized MCh, delivered to the alveoli, will increase the tissue elastic and dissipative properties, as well as increasing Raw if the delivered dose is high enough. Several studies, performed in various species, have reported that the pulmonary tissues are more sensitive than the airways to aerosolized MCh (18, 27). Because the presence and the location of the muscarinic subtype receptors have been shown to be species dependent (2), this mechanism may also explain the apparent species difference in the MCh responsiveness of the airways and the parenchyma.In an attempt to examine the mechanisms that give rise to an increase in Rti during MCh challenge, Nagase et al. (18) partitioned the response of the airways and the parenchyma after iv and aerosol administration of the agent by using alveolar capsules. They hypothesized that direct administration of the contractile agonist into the circulation should stimulate both the airway and parenchymal compartments homogeneously, whereas aerosol delivery would be likely to result in a heterogeneous airway response. Presenting histological evidence, they interpreted the higher increase in Rti after aerosol challenge as being due to the excessive tissue distortion, induced by heterogeneous constriction of the peripheral airways. However, in contrast to our result, they found a significant increase in the parenchymal elastance after MCh infusion. Another possible interpretation of our results is that MCh induced solely airway responses, regardless of the route of delivery. After an aerosol challenge, the uneven distribution of the particles around the bronchial tree could induce a heterogeneous peripheral airway response. This mechanism has been shown to generate a significant tissue distortion, i.e., the more sensitive regions or those regions to which the delivery is greater can be extremely constricted or even atelectatic, whereas adjacent regions can be hyperinflated (18). Obviously, this regional diversity after an aerosol challenge may significantly influence the estimation of the parenchymal mechanics by alveolar capsules because the sampling of the alveolar region is highly nonrepresentative and limited to subpleural areas. Should it occur to a significant degree, this phenomenon may also bias our parenchymal parameters, measured from the airway opening, in the following manner. The development of atelectatic regions may decrease the effective lung volume, resulting in increases in both Rti and EL (1). Additionally, hyperinflated regions adjacent to atelectatic areas can shift the operating volume of the working parenchyma toward its maximal volume, which would further increase the overall Rti and EL (1, 10, 28). The above analysis indicates that the apparent tissue constriction observed after aerosolized MCh could be produced by the excessive parenchymal distortion induced by an inhomogenous response of the peripheral airways, especially at extreme levels of constriction (that were probably not reached in the present investigations).
In summary, the results of the present study have demonstrated that airway and parenchymal responses to MCh in the rat can be partitioned on the basis of low-frequency ZL data. The changing pattern of the airway and tissue parameters indicates that the predominant site of action of MCh depends on the route of delivery. An iv MCh infusion induced purely airway constriction, whereas aerosolized MCh administration gave rise to constriction both in the airways and in the parenchyma. Although it is possible that the latter effects could be produced by a highly inhomogeneous constriction of the peripheral airways that led to a loss in lung volume, true differences in airway and tissue responses to MCh, possibly acting via different receptors, also seem very likely.
ACKNOWLEDGEMENTS
This study was supported by National Health and Medical Research Council of Australia Grant 960167 and the Hungarian Basic Research Fund (OTKA T016308).
FOOTNOTES
Address for reprint requests: Z. Hantos, Dept. of Medical Informatics and Engineering, Albert Szent-Györgyi Medical Univ., PO Box 2009, H-6701 Szeged, Hungary.
Received 16 August 1996; accepted in final form 15 January 1997.
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