Departments of Large Animal Clinical Sciences and Physiology, Michigan State University, East Lansing, Michigan 48824-1314
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ABSTRACT |
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To evaluate the functional status of neuronal
2-adrenoceptors
(ARs) and
2-ARs on
ACh release in horses with recurrent airway obstruction (RAO), we
examined the effects of the physiological agonists epinephrine
(Epi) and norepinephrine (NE) and the
2-agonists RR- and
RR/SS-formoterol
on ACh release from airway cholinergic nerves of horses with RAO.
Because SS-formoterol, a distomer of the
2-agonist, increases ACh
release from airways of control horses only after the autoinhibitory
muscarinic receptors are blocked by atropine, we also tested the
hypothesis that if there is an
M2-receptor dysfunction in equine
RAO, SS-formoterol should increase ACh
release even in the absence of atropine. ACh release was evoked by
electrical field stimulation and measured by HPLC. Epi and NE caused
less inhibition of ACh release in horses with RAO than in control
horses. At the catecholamine concentration achieved during exercise
(10
7 M), the inhibition
induced by Epi and NE was 10.8 ± 13.2 and 3.4 ± 6.8%,
respectively, in equine RAO versus 41.0 ± 6.4 and 27.1 ± 5.6%,
respectively, in control horses. RR-
and
RR/SS-formoterol (10
8 to
10
5 M) increased ACh
release to a similar magnitude as that in control horses. These results
indicate that neuronal
2-ARs
are functioning; however, the
2-ARs are dysfunctional in the
airways of horses with RAO in response to circulating catecholamines.
SS-formoterol (10
8 to
10
5 M) facilitated ACh
release in horses with RAO even in the absence of atropine. Addition of
atropine did not cause significantly more augmentation of ACh release
over the effect of SS-formoterol alone. The magnitude of augmentation in horses with RAO in the absence
of atropine was similar to that in control horses in the presence of
atropine. The latter observations could be explained by neuronal
muscarinic-autoreceptor dysfunction in equine RAO.
adrenoceptor; prejunctional; muscarinic receptor; catecholamine; formoterol; enantiomer; autoreceptor
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INTRODUCTION |
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ACUTE EXACERBATIONS of recurrent airway obstruction (RAO) of horses are characterized by bronchospasm, inflammation of the tracheobronchial tree, and nonspecific airway hyperresponsiveness (14). The rapid decrease in pulmonary resistance and increase in dynamic compliance after muscarinic blockade with atropine indicates that a large part of the bronchospasm is mediated through cholinergic mechanisms (3).
The release of ACh from equine airway cholinergic nerves is inhibited
prejunctionally by an inhibitory
2-adrenoceptor (AR) (20,
22) and an autoinhibitory muscarinic receptor (18). Dysfunction of these receptors may result in an exaggerated release of
ACh, an airway spasmogen, and contribute to the tracheobronchial constriction and hyperresponsiveness in horses with RAO. In normal horses, the
2-AR is activated
by levels of circulating catecholamines achieved during exercise (16,
22). Wang et al. (19) have previously demonstrated that
the inhibitory effect of the
2-AR agonist clonidine on ACh
release is lacking in bronchi and less potent in the trachea of horses
with RAO. We wanted to know whether the
2-AR dysfunction is reflected
in the response to endogenous catecholamines. Therefore, in the first
protocol of the present study, we examined the effect of epinephrine
(Epi; 10
8 to
10
5 M) and norepinephrine
(NE; 10
8 to
10
5 M) on ACh release from
airway parasympathetic nerves of horses with RAO.
Zhang and colleagues (21, 22, 24, 25) were the first to report an
excitatory 2-AR in airway
parasympathetic nerves. After their report in the horse, this receptor
was subsequently reported in guinea pig (2) and human airway
parasympathetic nerves (5). In airway preparations of control horses,
activation of
2-ARs by
isoproterenol, by the racemic mixture of specific
2-agonists such as albuterol
and formoterol, or by R-enantiomers of
2-agonists can increase ACh
release in a concentration-dependent manner. The maximal augmentation
resulting from activation of
2-ARs is approximately twofold
(21, 22, 24, 25). To evaluate the neuronal
2-AR function in horses with
RAO, in the second protocol of our present study, we examined the
effect of the racemic mixture of formoterol
(RR/SS-enantiomer)
and RR-formoterol on ACh release from
tracheal parasympathetic nerves of horses with RAO.
The prejunctional muscarinic autoreceptor provides negative feedback on
airway cholinergic nerves, and these receptors are dysfunctional in
guinea pigs challenged by ovalbumin (9) or infected with parainfluenza
virus (8) and in human asthmatic patients (13). However, the functional
status of neuronal M2 receptors in
equine RAO is still unknown.
SS-formoterol, a distomer of the
2-AR agonist, increases ACh
release in the control horses only in the presence of muscarinic
blockade with atropine, i.e., when neuronal
M2 receptors are dysfunctional
(24). Therefore, in the third protocol of the present study, we tested
the hypothesis that if there is a prejunctional
M2-receptor dysfunction in horses with RAO, SS-formoterol should
increase ACh release even in the absence of muscarinic blockade with atropine.
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MATERIALS AND METHODS |
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Animals. The study was approved by the All-University Committee on Animal Use and Care of Michigan State University (East Lansing). Six horses (body wt 481.7 ± 29.0 kg, age 14.5 ± 1.2 yr) with RAO during acute exacerbation were studied. Several days before the experiment, the RAO-susceptible horses were transferred from the pasture to stalls where they were fed dusty hay (6). They remained in the stalls until clinical signs of airway obstruction, such as flared nostrils and forced abdominal effort during expiration, were observed.
Tissue preparation. The animals were euthanized by injection of an overdose of pentobarbital sodium through the jugular vein. Other investigators also used tissues from the same animals for a variety of studies. Postmortem examination revealed that the lungs remained inflated when the chest was opened, and plugs of mucus and exudate were observed in the airways of all the animals. A segment of the trachea between the 16th and 30th cartilaginous rings above the carina was quickly collected, immersed in Krebs-Henseleit (KH) solution (composition in mM: 118.4 NaCl, 25.0 NaHCO3, 11.7 dextrose, 4.7 KCl, 2.6 CaCl2 · 2H2O, 1.19 MgSO4 · 7H2O, and 1.16 KH2PO4), and gassed with 95% O2-5% CO2 during the whole experiment. The trachea was opened longitudinally in its anterior aspect by dissection of the cartilages and was pegged flat on a paraffin block submerged in KH solution. Tracheal smooth muscle strips with the epithelium intact were cut with a template along the fiber direction before being suspended in tissue baths. The temperature within the baths was maintained at 37°C, and the KH solution was changed every 15 min. Square-wave electrical impulses were produced by a stimulator (S88, Grass Instruments, Quincy, MA) and passed through a stimulus power booster (Stimu-Splitter II, Med-Lab Instruments, Loveland, CO) to electrodes in the tissue baths.
Measurement of electrical field stimulation-induced
ACh release. Four tissue strips (each measuring 2 × 15 mm) were cut and tied together at both their ends with 3-0 surgical silk thread. Each trachealis strip bundle (wet weight 217.3 ± 3.3 mg; n = 72 strips) was
suspended in a 2-ml tissue bath with a pair of parallel platinum wire
electrodes built against the wall of the bath in the vertical direction
(Radnoti Glass Technology, Monrovia, CA). One end of the tissue strip
was secured to the bottom of the bath with a glass tissue holder; the
other end was attached to an 8-g weight via a surgical thread that
passed over a steel bar above the tissue bath (17). After an ~120-min
equilibration period, the tissues were incubated for 60 min with the
cholinesterase inhibitor neostigmine
(106 M) and the sympathetic
nerve blocker guanethidine
(10
5 M) with and without
the muscarinic-autoreceptor antagonist atropine (10
7 M). These agents were
present during the remainder of the experiment.
The ACh concentration in the tissue bath liquid was measured by HPLC coupled with electrochemical detection. The mobile phase contained 100 mM Na2HPO4 (pH 8.0), and the flow rate was 0.35 ml/min. The samples were filtered through 0.2-µm nylon membrane filters (Acrodiscs 13, Gelman Sciences, Ann Arbor, MI) and injected into the HPLC column at a volume of 25 µl/injection. An external ACh standard (2.5 pmol in 25 µl) was injected into every six samples, and the concentration of ACh in the samples was calculated based on the bracketed calibration (for details of this technique, see Refs. 17, 22).
Study design. Electrical field stimulation (EFS; 0.5 Hz, 0.5 ms, 20 V) was applied to all the tissues for five 15-min periods, with a 30-min resting interval between consecutive stimuli. During the first EFS, we determined the baseline release of ACh. The tested drugs were then added to the baths 10 min before subsequent EFS. To eliminate any ACh that may have been released during the incubation period (17), the tissue baths were drained and refilled with fresh KH solution containing the tested drugs immediately before EFS was begun. The tissue bath solution was collected on the completion of each EFS for the measurement of ACh. The tissues were rinsed four times with the KH solution immediately after collection of the samples. At the end of the experiment, the tissues were blotted dry and weighed.
Protocol 1: Effects of Epi and NE on EFS-induced ACh
release from trachealis cholinergic nerves of horses with
RAO. Three tissue-strip bundles from each horse were
used in the presence of the muscarinic-receptor blocker atropine. One
did not receive tested drug treatment and served as the time control.
The second and third tissue-strip bundles each received Epi
(108 to
10
5 M) and NE
(10
8 to
10
5 M). The results of the
effects of Epi and NE on ACh release obtained from the horses with RAO
were compared with those of control horses in a previously published
study from our laboratory (22).
Protocol 2: Effects of RR- and RR/SS-formoterol on
EFS-induced ACh release from trachealis cholinergic nerves of horses
with RAO. Six tissue-strip bundles from each horse were
used. Three tissue-strip bundles were used in the absence of the
muscarinic-receptor blocker atropine. One did not receive
2-agonists and served as the
time control. The remaining two received either
RR- or
RR/SS-formoterol (10
8 to
10
5 M) after the first EFS.
A similar protocol was repeated with the other three tissue-strip
bundles in the presence of muscarinic-receptor blockade with atropine
(10
7 M). The magnitude of
augmentation of ACh release in horses with RAO was compared with that
in control horses (24) to evaluate the neuronal
2-AR function in horses with RAO.
Protocol 3: Effects of SS-formoterol on EFS-induced
ACh release from trachealis cholinergic nerves of horses with
RAO. Four tissue-strip bundles from each horse were
used. Two tissue-strip bundles were used in the absence of the
muscarinic-receptor blocker atropine. One did not receive
SS-formoterol and served as the time
control. The other received
SS-formoterol
(108 to
10
5 M). A similar protocol
was repeated with the other two tissue-strip bundles in the presence of
muscarinic-receptor blockade with atropine (10
7 M). The results of the
effects of SS-formoterol on ACh
release obtained from the horses with RAO were compared with those of control horses (24) to evaluate the neuronal muscarinic function in
horses with RAO.
Drugs. Atropine sulfate, acetylcholine chloride, neostigmine methylsulfate, guanethidine monosulfate (all from Sigma, St. Louis, MO), and enantiomers of formoterol (Sepracor, Marlborough, MA) were dissolved and diluted in KH solution. Epinephrine bitartrate and norepinephrine hydrochloride (Sigma) were dissolved and diluted in a 0.1% ascorbate solution. All the drugs were prepared on the day of the experiment. The drug solution was pipetted into the tissue bath at 1% of the bath volume. The final concentration of the drugs was expressed as their bath molar concentration.
Data analysis. The results of the
present study obtained from horses with RAO were compared with data
from historical control horses studied by the same personnel in the
same laboratory. The ACh release rate is expressed in both picomoles
per gram per minute and a percentage of baseline (first EFS without
drug treatment). Means ± SE for all parameters were calculated;
n is the number of horses studied
except where otherwise specified. The percent inhibition of Epi and NE
at each concentration (108
to 10
5 M) on ACh release in
horses with RAO was compared with that in control horses (22) with
unpaired Student's t-test. The other data were evaluated by repeated-measures ANOVA and ANOVA with contrasts
with Statview II (Abacus Concepts, Calabasas, CA) for the Macintosh
computer. Means were compared by Fisher's (protected) least
significant difference test. P < 0.05 was considered significant.
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RESULTS |
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In the absence of atropine, EFS-induced baseline ACh release averaged
1.55 ± 0.11 pmol · g1 · min
1
(n = 24 strips). This value was not
significantly different from that in the control horses (1.39 ± 0.08 pmol · g
1 · min
1;
Ref. 24). In the presence of blockade of muscarinic receptors with
atropine (10
7 M),
EFS-induced baseline ACh release reached 5.23 ± 0.27 pmol · g
1 · min
1
(n = 48 strips). This rate of ACh
release is similar to that in the control horses (5.50 ± 0.35 pmol · g
1 · min
1;
Ref. 24).
Protocol 1: Effects of Epi and NE on EFS-induced ACh
release from trachealis cholinergic nerves of horses with
RAO. In time-control tissues of horses with RAO, ACh
release remained constant throughout the five stimulations. Although
the maximal inhibition was similar to that in the control horses (22),
the response curve to both Epi and NE was shifted to the right in
RAO-affected animals. Epi and NE caused a significant inhibition of ACh
release only at the concentrations of
106 and
10
5 M but not at
10
7 M or lower (Fig.
1). Figure 2
compares the percent inhibition of ACh release by Epi and NE in airways
of control horses (22) and horses with RAO. At the catecholamine
concentrations achieved during exercise
(10
7 M), the inhibition
induced by Epi and NE was 10.8 ± 13.2 and 3.4 ± 6.8%,
respectively, in RAO-affected horses
(n = 6). However, in the control
horses, the inhibition was 41.0 ± 6.4 and 27.1 ± 5.6%,
respectively (22). The differences were significant (Fig. 2).
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Protocol 2: Effects of RR- and RR/SS-formoterol on
EFS-induced ACh release from trachealis cholinergic nerves of horses
with RAO. In the absence of atropine, ACh release from
time-control tissues remained constant throughout the five
stimulations. RR- and
RR/SS-formoterol
augmented ACh release in a concentration-dependent manner (Fig.
3A). The
augmentation reached significance at the concentration of
108 M for both
RR- and
RR/SS-formoterol.
At the concentration of 10
6
M, RR- and
RR/SS-formoterol
increased ACh release to 199.3 ± 24.6 and 187.5 ± 8.8%,
respectively, of baseline (n = 6 animals). This magnitude is similar to that in the control horses
(181.9 ± 9.1 and 187.7 ± 22.7%, respectively, of baseline;
Ref. 24). In the presence of atropine,
RR- and
RR/SS-formoterol
also increased ACh release in a concentration-dependent manner (Fig.
3B). The maximal augmentation, i.e.,
an approximate doubling of ACh release that was reached at a
concentration of 10
7 M for
both RR- and
RR/SS-formoterol,
was of similar magnitude to that in the control horses (24).
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Protocol 3: Effects of SS-formoterol on EFS-induced
ACh release from trachealis cholinergic nerves of horses with
RAO. In the control horses,
SS-formoterol
(108 to
10
5 M) had no effect on ACh
release in the absence of atropine. However, SS-formoterol dose dependently
facilitated ACh release in the presence of atropine, and at the
concentration of 10
5 M,
SS-formoterol increased the release to
166.1 ± 7.7% of baseline (Fig.
4A; Ref.
24). In the horses with RAO,
SS-formoterol
(10
8 to
10
5 M) increased ACh
release even in the absence of atropine (Fig. 4B). At the concentration of
10
5 M,
SS-formoterol increased ACh release to
172.3 ± 13.5% of baseline (n = 6 animals). The magnitude of augmentation in the absence of atropine in
horses with RAO (Fig. 4B) was
similar to that in the control horses in the presence of atropine (Fig.
4A; Ref. 24). The addition of atropine
slightly but not significantly increased ACh release over the effect of
SS-formoterol alone (Fig. 4B).
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DISCUSSION |
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The effect of catecholamines on ACh release from equine airway
parasympathetic nerves is mediated by both
2-inhibitory and
2-excitatory adrenoceptors,
with the former being predominant (22). The sympathoadrenal discharge
of the horse increases the mean plasma concentrations of Epi and NE
from 9 ± 10
10 and 7 ± 10
10 M, respectively,
at rest, to 1.53 ± 10
7
and 1.48 ± 10
7 M,
respectively, during exercise (16). In a previous study, Zhang et al.
(22) demonstrated that both Epi and NE at concentrations of
10
8 to
10
5 M dose dependently
inhibited ACh release from airway parasympathetic nerves of control
horses and that these inhibitions are mediated via
2-ARs. In our present study, we
demonstrated that at the catcholamine concentration achieved during
exercise (10
7 M), the
inhibition induced by Epi and NE was significantly less in horses with
RAO than in control horses. This decreased inhibitory effect of
catecholamines may be due to the increased rate of catecholamine metabolism by the smooth muscle of our tissue preparations in horses
with RAO. However, this is unlikely because Wang et. al. (19) from our
laboratory demonstrated that clonidine, a pharmacological
2-AR agonist that is
inactivated independent of catecholamine metabolic pathways, also
possesses less inhibitory effect on ACh release from RAO-affected
horses. Because Epi can activate both an inhibitory
2-AR and an excitatory
2-AR (22), the decreased inhibition of Epi on ACh release may also be due to either a decreased inhibitory effect of
2-AR, an
increased facilitatory effect of
2-AR, or a combination of both.
However, our results demonstrated that in airway parasympathetic nerves
of the RAO-affected horse, activation of
2-ARs with both
RR- and
RR/SS-formoterol
(10
8 to
10
5 M) increased ACh
release with a similar magnitude as that in control horses (24). This
result indicated the absence of prejunctional
2-AR dysfunction in airway
parasympathetic nerves of horses with RAO. Therefore, attenuated
inhibition of Epi on ACh release from RAO-affected animals must be due
to the dysfunction of prejunctional inhibitory
2-ARs. Because the inhibitory
effect of NE is solely mediated via
2-ARs (22), decreased
NE-induced inhibition of ACh release from RAO-affected animals provides
additional evidence of prejunctional
2-AR dysfunction. Combining all
the above evidence, we conclude that the prejunctional
2-AR is dysfunctional in horses with RAO and that this
2-AR
dysfunction is reflected in the response to endogenous catecholamines
(16). However, the function of prejunctional
2-ARs is normal.
In the control horses, Zhang et al. (24) have previously demonstrated
that SS-formoterol, a distomer of the
2-agonist, facilitates ACh
release in the presence of atropine, which blocks the prejunctional
muscarinic autoinhibitory receptor, but not in the absence of atropine
when the neuronal muscarinic autoinhibitory receptor is functional
(Fig. 4A). Therefore, we
hypothesized that if the prejunctional
M2 receptors are dysfunctional in
equine RAO, SS-formoterol should
increase ACh release even in the absence of muscarinic blockade with
atropine. In support of this hypothesis, our results revealed that
SS-formoterol facilitated ACh release in the absence of atropine and that the magnitude of augmentation in
the horses with RAO in the absence of atropine was similar to that in
the control horses in the presence of atropine. Furthermore, in the
RAO-affected horses, blockade of muscarinic receptors by atropine did
not cause significantly more augmentation of ACh release over the
effect of SS-formoterol alone (Fig.
4B). These observations suggest that
the prejunctional muscarinic autoreceptors in airway parasympathetic
nerves of horses with RAO are dysfunctional.
The neuronal autoinhibitory M2 receptors are also dysfunctional in ovalbumin-sensitized guinea pig airway parasympathetic nerves after antigen challenge (9), in virus-infected guinea pigs (8), and in ozone-challenged guinea pigs (15) and also may be dysfunctional in some asthmatic patients (13). However, the pathogenesis of M2-receptor dysfunction is different in the different diseases. In antigen-challenged guinea pigs (12) and human asthmatic patients (4), there is a large influx of eosinophils in the airway. These eosinophils and their major basic protein, an antagonist for M2 receptor (12), are especially associated with airway nerves (4). In virus-infected guinea pigs, viruses have both an indirect leukocyte-dependent effect and a leukocyte-independent effect on M2 receptors (10). In ozone-challenged guinea pigs, leukocytes or mediators are important in the pathogenesis of the loss of M2-receptor function (11). Equine RAO is a delayed hypersensitivity response to inhaled antigen, particularly the thermophilic molds and actinomycetes that grow in damp hay (14), and is characterized by a predominant neutrophilic inflammation with few eosinophils as revealed by bronchoalveolar lavage (7). However, the role of inflammation or mediators in the development of neuronal M2-receptor dysfunction in equine RAO is unknown, and further investigations are needed.
Despite the apparent M2-receptor
dysfunction, we noticed that the magnitude of
RR- and
RR/SS-formoterol-induced
augmentation of ACh release was similar in the two groups of animals
and that the amount of ACh release evoked by EFS in picomoles per gram per minute in equine RAO was not different from that in the control horses. Why should the neuronal
M2-receptor dysfunction be
reflected only in the response to
SS-formoterol, a weak
2-agonist, but not in the
response to the potent
2-agonists
(RR- and
RR/SS-formoterol) or EFS-induced baseline ACh release? Previous studies in airway parasympathetic nerves (23) and the myenteric plexus (1) suggest that
neuronal M2 receptor-mediated
inhibition of ACh release is via at least two different intracellular
mechanisms: cAMP-dependent and cAMP-independent pathways, with the
latter predominant, whereas the facilitation of ACh release by
2-AR agonists involves only cAMP-dependent pathways (23). These two pathways are diagrammed in Fig.
5. If neuronal
M2-receptor dysfunction in equine
RAO affects the cAMP-dependent but not the cAMP-independent pathway,
the dysfunction of the M2
receptors would be reflected primarily in their responses to agents
that act via intracellular cAMP. Under this scenario, activation of
2-AR by a weak agonist,
SS-formoterol, has no effect in
control horses because the ACh released during EFS activates the
cAMP-dependent autoinhibitory mechanism and prevents the
2-AR agonist-induced increase
in cAMP (Fig. 5). However, when the cAMP-dependent autoinhibitory
pathway is dysfunctional, the weak agonist increases cAMP and
facilitates release. Such is the situation in RAO-affected horses and
in control horse tissue after atropine treatment. By contrast, when the
2-ARs are activated by full
2-AR agonists such as
RR- and
RR/SS-formoterol,
the increase in intracellular cAMP cannot be overridden by the
relatively weak cAMP-dependent M2-receptor autoinhibitory pathway
and ACh release increases. In this situation,
M2-mediated inhibitory
cAMP-dependent pathway dysfunction is irrelevant because the
autoinhibition of cAMP production is trivial in comparison to the major
increase in cAMP engendered by the strong
2-AR agonist.
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A similar explanation can be used to explain the absence of a
difference in EFS-induced ACh release between tissues from control and
RAO-affected horses, the fact that atropine still increases ACh release
in such horses, and even the dysfunction of the prejunctional inhibitory 2-AR. If the primary
M2-receptor mechanism is cAMP independent and there is dysfunction only in the cAMP-dependent pathway, it will be very difficult to detect differences in release between diseased and control horses, and atropine will still block the
activation of the cAMP-independent pathway and therefore increase ACh
release (Fig. 5). As with the M2
receptor, the prejunctional inhibitory
2-AR acts primarily via
cAMP-independent pathways but to a small degree via cAMP-dependent
pathways (26). Dysfunction solely in the latter pathway may explain the
reduced inhibition of ACh release by lower concentrations of Epi and NE
in RAO-affected animals.
In conclusion, the present study demonstrated in the airway of
RAO-affected horses that 1) the
prejunctional inhibitory 2-AR is dysfunctional, which may lead to less inhibition of bronchospasm in
exercising horses with RAO; 2)
neuronal
2-AR function is
normal; and 3)
SS-formoterol-mediated augmentation of
ACh release in the absence of atropine could be explained by neuronal
M2-receptor dysfunction.
Therefore, dysfunction of prejunctional receptors is not a generalized
effect but may be restricted to specific pathways.
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ACKNOWLEDGEMENTS |
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We thank Cathy Berney for technical assistance and Victoria Hoelzer-Maddox and MaryEllen Shea for manuscript preparation.
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FOOTNOTES |
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This work was supported in part by an endowment from the Matilda R. Wilson Fund and by Sepracor, Inc.
X.-Y. Zhang is a fellow of the American Lung Association of Michigan.
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 and other correspondence: N. E. Robinson, Dept. of Large Animal Clinical Sciences, Michigan State Univ., East Lansing, MI 48824-1314 (E-mail: Robinson{at}cvm.msu.edu).
Received 21 September 1998; accepted in final form 25 January 1999.
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