Department of Molecular Pharmacology, University of Groningen, 9713 AV Groningen, The Netherlands
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ABSTRACT |
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Using electrical field stimulation of
epithelium-denuded intact guinea pig tracheal tube preparations, we
studied the presence and role of prejunctional
2-adrenoceptors by
measuring evoked endogenous acetylcholine (ACh) and norepinephrine (NE)
release directly. Analysis of ACh and NE was through two HPLC systems with electrochemical detection. Electrical field stimulation (150 mA,
0.8 ms, 16 Hz, 5 min, biphasic pulses) released 29.1 ± 2.5 pmol
ACh/g tissue and 70.2 ± 6.2 pmol NE/g tissue. Preincubation for 15 min with the selective
2-adrenoceptor agonist
fenoterol (1 µM) increased both ACh and NE overflow to 178 ± 28 (P < 0.01) and 165 ± 12%
(P < 0.01), respectively, of control
values, increases that were abolished completely by the selective
2-adrenoceptor antagonist
ICI-118551 (1 µM). Further experiments with increasing fenoterol
concentrations (0.1-100 µM) and different preincubation periods
(1, 5, and 15 min) showed a strong and concentration-dependent facilitation of NE release, with maximum response levels decreasing (from nearly 5-fold to only 2.5-fold of control value) with increasing agonist contact time. In contrast, sensitivity of facilitatory
2-adrenoceptors on cholinergic
nerves to fenoterol gradually increased when the incubation period was
prolonged; in addition, a bell-shaped concentration-response
relationship was found at 15 min of preincubation. Fenoterol
concentration-response relationships (15-min agonist preincubation) in
the presence of atropine and yohimbine (1 µM each) were similar in
the case of NE release, but in the case of ACh release, the bell shape
was lost. The results indicate a differential capacity and response
time profile of facilitatory prejunctional
2-adrenoceptors on adrenergic
and cholinergic nerve terminals in the guinea pig trachea and suggest that the receptors on adrenergic nerves are more susceptible to desensitization.
facilitatory prejunctional
2-adrenoceptors; acetylcholine
release; norepinephrine release
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INTRODUCTION |
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THE AIRWAYS OF MANY SPECIES are innervated by both parasympathetic and sympathetic neural pathways. The physiological effect of the parasympathetic nerves, which use acetylcholine (ACh) as a neurotransmitter, is excitatory, causing airway constriction. On the other hand, the sympathetic innervation for which norepinephrine (NE) is the neurotransmitter is inhibitory, causing airway dilatation (21). As in other tissues, these airway neural systems may be subject to prejunctional control of neurotransmitter release.
Prejunctional -adrenoceptors were described for the first time by
Adler-Graschinsky and Langer (1) and by Stjärne (17), who found
that isoproterenol caused an increase of tritiated NE overflow evoked
by nerve stimulation of postganglionic adrenergic nerves in guinea pig
isolated atria and vas deferens, respectively. Although facilitatory
prejunctional
-adrenoceptors have been described in many central and
peripheral tissues since, both in vitro and in vivo (6, 13, 14),
conclusive information about such receptors in airways has been
somewhat controversial.
Originally, it was concluded that prejunctional
2-adrenoceptors exerted an
inhibitory influence on cholinergic neurotransmission in human airways.
This viewpoint emerged from indirect studies (2, 16) in which the
effects of
-adrenoceptor agonists on the contractile responses of
bronchial smooth muscle to electrical field stimulation (EFS) and
exogenous ACh were compared to discriminate between pre- and
postjunctional adrenoceptor effects. This technique, although useful,
is essentially indirect because it does not measure the actual release
of the neurotransmitter. With the use of the same technique, it has
been recently demonstrated in our laboratory that, at least in guinea
pig main bronchi, inhibitory
2-
or
3-adrenoceptors are not
functional on cholinergic nerve endings (18).
A more direct approach to investigate the existence and function of
prejunctional receptors is to measure the actual overflow of
neurotransmitters. With such a technique, inhibition of
[3H]ACh release
mediated by -adrenoceptors has been reported for isolated rat and
guinea pig tracheae, but this response required an intact epithelium
(20). On the other hand, direct, i.e., epithelium-independent,
2-adrenoceptor-mediated
facilitation of endogenous ACh release was observed in the equine
trachea (22, 23) and, more recently, in the guinea pig trachea (4).
-Adrenoceptor-mediated facilitation of NE release in the airways has
hitherto only been described in one report; i.e., in rat isolated
tracheae, an epithelium-dependent facilitation was observed (5).
In the present study, for the first time, the existence and function of
prejunctional 2-adrenoceptors
on both parasympathetic and sympathetic nerve endings in
epithelium-denuded guinea pig tracheae have been explored
simultaneously by measuring the EFS-evoked release of endogenous (i.e.,
not prelabeled) ACh and NE with two sensitive HPLC systems equipped
with electrochemical detection (ECD) that have been developed over the
past years (6, 14, 19). In these experiments, the nature and magnitude
of the response to a single concentration of the
2-adrenoceptor agonist
fenoterol were first established; subsequently, the
concentration-response relationships for fenoterol were characterized
in the absence and presence of auto- and heteroreceptor antagonists
(i.e., atropine and yohimbine) and at various agonist contact times.
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METHODS |
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Tissue preparation. Adult guinea pigs of either sex (Charles River, Kisslegg, Germany) weighing 600-800 g were killed by a sharp blow on the head, after which the tracheae were rapidly removed. The tracheae were placed in Krebs-Henseleit (KH) buffer solution (37°C) of the following composition (in mM): 117.50 NaCl, 5.60 KCl, 1.18 MgSO4, 2.52 CaCl2, 1.28 NaH2PO4, 25.00 NaHCO3, and 5.55 D-glucose, pH 7.4, aerated with 5% CO2-95% O2. The tracheae were prepared free of connective tissue, and the airway epithelium was carefully removed by moving a 15-cm woolen thread up and down the trachea twice. Subsequently, the tracheae were cut into four segments. To ensure comparable levels of neurotransmitter release, the proximal and distal parts provided one set of preparations and the two middle parts provided one set. The two tracheal segments were positioned over two platinum rod electrodes placed 0.7 cm apart in a water-jacketed tissue bath (37°C) in such a way that the smooth muscle layers were located between the electrodes as described by Ten Berge et al. (19).
Experimental protocol. All release
experiments were performed in the presence of 10 µM
L-tyrosine. No reuptake
inhibitors, acetylcholinesterase inhibitors, or auto- and
heteroreceptor antagonists were used unless stated otherwise. The
tracheal preparations were allowed to equilibrate for four 15-min
periods in 10.0 ml of fresh KH buffer, after which the tissues were
placed in 4.0 ml of fresh KH buffer. After 15 min, three
500-µl samples were taken to determine the spontaneous
release of ACh and NE. In the remaining 2.5 ml of KH buffer, EFS was
applied (16 Hz, 150 mA, 0.8 ms, biphasic square-wave pulses) for 5 min
[first episode of stimulation (S1)]. After
EFS, three 500-µl samples were taken. Subsequently, the preparations
were allowed to recover for 30 min in fresh KH buffer. All samples were
stored immediately at 20°C until analysis.
The first set of experiments started with three control episodes of
stimulation (S1-S3). After the 30-min recovery from the previous
stimulation episode, the selective
2-adrenoceptor agonist fenoterol (1 µM) was added and incubated for 15 min before the fourth
episode of stimulation (S4). The fifth episode of stimulation (S5) was
a control stimulation. Before the sixth episode of stimulation (S6),
the selective
2-adrenoceptor
antagonist ICI-118551 (1 µM) was added and incubated for 30 min, and
fenoterol (1 µM) was administered 15 min later. The seventh episode
of stimulation (S7) was a control stimulation. In each experiment,
control stimulations were run in parallel in tracheal preparations that
did not receive any
2-adrenoceptor agent.
In the second set of experiments, the concentration and incubation time dependence of the prejunctional effects of fenoterol were explored. As before, S1-S3 were performed in the absence of drugs. S4-S7 were performed in the presence of increasing concentrations of fenoterol (0.1-100 µM), with incubation times being 1, 5, or 15 min. Parallel control experiments in the absence of fenoterol were performed regularly.
The effects of 0.1-100 µM fenoterol (15-min agonist
preincubation) were also studied under conditions where auto- and
heteroregulation of neurotransmitter release, through prejunctional
muscarinic and 2-adrenoceptors,
was eliminated by coincubation with atropine and yohimbine (both at 1 µM). The antagonists were present from 30 min before S3 onward.
At the end of the experiments, the preparations were blotted and weighed. The amount of neurotransmitter released during stimulation is expressed in picomoles per gram of tissue per 5 min.
Measurement of released ACh. KH samples (300 µl) were injected into an HPLC-ECD system equipped with a reverse phase-based anion-exchange analytic column. The mobile phase contained 100 mM potassium phosphate buffer (pH 8.0) in ultrapure water filtered through a 0.2-µm membrane filter (Schleicher & Schuell, Dassel, Germany), and the flow rate was 0.35 ml/min. After separation, ACh was hydrolyzed in an immobilized enzyme reactor by acetylcholinesterase to choline, and the choline was subsequently oxidized by choline oxidase to betaine and hydrogen peroxide. Hydrogen peroxide was then detected with an electrochemical detector (Antec Leyden, Leiden, The Netherlands) set to an oxidation potential of +500 mV. The analytic column and immobilized enzyme reactor were prepared according to Damsma and Westerink (7) and Ten Berge et al. (19), with slight modification. Briefly, a guard and an analytic column (both 75 × 2.1 mm; Chrompack, Middelburg, The Netherlands) were prepared from Chromspher 5 C18 (Chrompack). The analytic column was then loaded with 0.5% sodium dodecyl sulfate. After being washed with water, the column was equilibrated overnight with the mobile phase. To prepare the enzyme reactor, an enzyme solution containing 80 U of acetylcholinesterase and 40 U of choline oxidase dissolved in 1 ml of the mobile phase was passed through a column containing Lichrosorb-NH2 (Merck, Darmstadt, Germany) activated with glutaraldehyde. Before use, the reactor was washed for 30 min with the mobile phase. The detection limit of the HPLC-ECD system was ~20 fmol ACh/injection.
Measurement of released NE. After extraction of 450-µl KH samples according to the method previously described (15), catecholamines were determined by HPLC-ECD. The column was an Alltech Adsorbosphere Catecholamine C18 3-µm cartridge (100 × 4.6 mm), and the mobile phase (pH 3.8) was composed of ultrapure water-methanol (97.0:3.0 vol/vol), 0.78% citric acid, 0.68% NaH2PO4, 0.02% octane sulfonic acid, and 0.01% EDTA. This solution was filtered through a 0.2-µm membrane filter (Schleicher & Schuell). The flow rate was set at 1.00 ml/min. An Environmental Sciences Associates Coulochem 5100 A electrochemical detector with a 5011 high-sensitivity analytic cell set to an oxidation potential of +350 mV was used for the detection of catecholamines. Correction for incomplete recovery was applied with 3,4-dihydroxybenzylamine as an internal standard. The detection limit of the HPLC-ECD system was ~4 fmol NE/injection.
Drugs. The following substances were used: ICI-118551 hydrochloride (Zeneca Pharmaceuticals, Macclesfield, UK), 3,4-dihydroxybenzylamine hydrobromide, ACh chloride, acetylcholinesterase (EC 3.1.1.7), choline oxidase (EC 1.1.3.17), fenoterol hydrobromide, and NE hydrochloride (Sigma, St. Louis, MO). All other chemicals were of reagent grade and obtained from standard sources.
Statistical analysis. ACh and NE release are expressed as a percentage of the release after S3, and means ± SE were calculated for all data. Single-dose fenoterol effects were evaluated by one-way analysis of variance with a post hoc Student-Newman-Keuls test. When below the 0.05 level of probability, the actual level of significance was calculated by Student's t-test. Cumulative effects of fenoterol were evaluated by repeated-measures analysis of variance with a post hoc Student-Newman-Keuls test. When below the 0.05 level of probability, the actual level of significance was calculated by Student's paired t-test.
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RESULTS |
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Basal levels of EFS-induced ACh and NE
release. EFS (150 mA, 16 Hz, and 0.8 ms for 5 min)
evoked the release of ACh and NE from autonomic nerve endings in guinea
pig tracheal smooth muscle. Control ACh release, i.e., during S3,
averaged 29.1 ± 2.5 pmol · g
tissue1 · 5 min
1
(n = 46 experiments), and control NE
release averaged 70.2 ± 6.2 pmol · g
tissue
1 · 5 min
1
(n = 48 experiments; see
Fig. 1 for chromatograms).
Spontaneous release of either neurotransmitter was not observed.
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Effects of fenoterol and ICI-118551 on EFS-induced ACh
and NE release. The release of both ACh and NE remained
fairly constant throughout the seven stimulation episodes in control
preparations, the ACh and NE release at S7 being 93 ± 6 (n = 6 experiments) and 93 ± 14%
(n = 6 experiments), respectively, of
the release at S3, indicating negligible exhaustion of neurotransmitter
pools. Pretreatment of guinea pig tracheal segments with 1 µM
fenoterol for 15 min before S4 resulted in an enhanced overflow of both ACh and NE (Fig. 2). The EFS-evoked
overflow of ACh was augmented by 78.1 ± 27.5%
(P < 0.01;
n = 6 experiments), whereas the
overflow of NE was augmented by 65.3 ± 11.8%
(P < 0.01;
n = 6 experiments) compared with S3.
To confirm that these facilitations were induced by activation of
2-adrenoceptors, the effect of
1 µM ICI-118551 was studied. It was found that ICI-118551 completely
abolished the facilitatory effect of fenoterol alone and that the
remaining overflow of both ACh and NE was not significantly different
from that in control tracheal preparations (Fig. 2). ICI-118551 by itself did not affect neurotransmitter overflow (data not shown).
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Effects of agonist exposure time and concentration on
EFS-induced ACh and NE release. The relative
sensitivity of the facilitatory prejunctional
2-adrenoceptors was
investigated by studying the concentration dependency to fenoterol
(0.1-100 µM) at different preexposure times (1, 5, and 15 min;
Figs. 3 and 4). With a 1-min preincubation, fenoterol from 1 to 100 µM concentration dependently enhanced evoked ACh overflow, whereas 0.1 µM fenoterol was still without effect; however, with 10 and 100 µM fenoterol, facilitation reached significance. With the 5-min preincubation period, the facilitatory responsiveness of the prejunctional
2-adrenoceptors had increased;
the maximum effect was already reached at 1 and 10 µM fenoterol,
whereas with 100 µM fenoterol, facilitation tended to diminish. With
a 15-min exposure time, sensitivity was further increased; significant
facilitation of a magnitude similar to the maximum effect reached with
the 5-min incubation of 1 µM of the agonist was already seen with 0.1 µM fenoterol. Facilitation after 15 min increased further with 1 µM
fenoterol, whereas at higher fenoterol concentrations, particularly 100 µM, the facilitatory effect diminished, resulting in a clear
bell-shaped concentration-response relationship (Fig. 3).
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NE overflow showed a concentration-dependent facilitation after
pretreatment with fenoterol at all agonist exposure periods. In
contrast to ACh overflow, highest facilitation was observed with the
shorter preincubation times; moreover, the capacity of the
prejunctional 2-adrenoceptors
to facilitate NE overflow was much stronger, reaching levels of
~500% of the control level at the highest fenoterol concentration
(100 µM, 1 min; Fig. 4).
Effect of a 15-min agonist exposure on EFS-induced ACh
and NE release in the presence of auto- and heteroreceptor
inhibitors. In the presence of atropine and yohimbine
(both 1 µM), fenoterol facilitated the evoked ACh release to a
similar extent as in the absence of these receptor antagonists (Fig.
5). The decreased facilitation with higher agonist
concentrations was no longer observed, however. NE release again showed
a concentration-dependent facilitation in response to fenoterol, the
effect being slightly greater in the presence of atropine and yohimbine
(Fig. 5).
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DISCUSSION |
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The present study was designed to establish whether and to what extent
endogenous ACh and NE release from parasympathetic and sympathetic
nerve endings, respectively, are under prejunctional control of
2-adrenoceptors in
epithelium-denuded guinea pig tracheae. With the use of the
2-adrenoceptor agonist
fenoterol and the
2-adrenoceptor antagonist
ICI-118551, we demonstrated that both parasympathetic and sympathetic
nerve endings in the guinea pig trachea are equipped with facilitatory
2-adrenoceptors (Fig. 2). Among
these, especially those on the adrenergic nerve endings were able to
induce a large facilitation of neurotransmitter (NE) release (Fig. 4).
Concentration-response and agonist contact time relationships were
markedly different between ACh and NE release (Figs. 3-5).
In these experiments, we measured the simultaneous release of endogenous ACh and NE in the absence of acetylcholinesterase inhibitors and inhibitors of neuronal or extraneuronal norepinephrine uptake. Considering the relatively long duration, the experiments were performed in the presence of tyrosine, however (compare with Ref. 5). Choline preincubation was not applied because in a recent study, Ten Berge et al. (19) found this precursor to have no influence at all on the enhancement of endogenous ACh release induced by atropine even after repeated administration.
The present findings of facilitatory
2-adrenoceptors on cholinergic
nerve endings differ from earlier reports (2, 16, 20)
where inhibitory
2-adrenoceptor-mediated control
over ACh release was described. Such inhibitory adrenoceptors were
demonstrated in guinea pig and rat tracheae and appeared to be located
in the airway mucosa because the isoproterenol-induced inhibition of stimulated [3H]ACh
release was no longer present after removal of this mucosa (20). In the
present experiments, such indirect effects can be excluded because the
tracheal preparations were carefully denuded of epithelium, which was
checked histologically on several occasions. Our finding of
prejunctional facilitatory
2-adrenoceptors on cholinergic
nerve endings in the guinea pig trachea is in line, however, with
observations in the equine trachea, where isoproterenol concentration
dependently increased EFS-evoked endogenous ACh release (22, 23).
Recently,
2-adrenoceptor-mediated
facilitation of
[3H]ACh release from
the guinea pig trachea has also been described (4).
A direct facilitatory effect of -adrenoceptor agonist on EFS-evoked
NE overflow from sympathetic nerves in the guinea pig trachea has not
been previously reported. An indirect effect was observed in the
isolated rat trachea, however, where isoproterenol augmented the
EFS-induced NE release in the presence but not in the absence of the
mucosa in an indomethacin-sensitive fashion (5). As mentioned above,
our experimental setup ruled out the possibility of such indirect effects.
Interesting differences in the facilitatory responses to fenoterol were
observed between cholinergic and adrenergic nerves. When the agonist
preincubation time was prolonged from 1 to 15 min, the response of the
prejunctional 2-adrenoceptors
to facilitate ACh overflow increased; at the same time, the
concentration-response relationship gradually attained a bell-shaped
nature. To investigate whether counterregulation by prejunctional
M2 muscarinic and
2-adrenergic auto- and
heteroreceptors was responsible for or contributed to the diminished
facilitation seen with a 15-min preincubation with 10 and 100 µM
compared with 1 µM fenoterol, concentration-response relationships
were also established in the presence of atropine and yohimbine. As
shown in Fig. 5, the facilitation obtained with the two higher
fenoterol concentrations remained very similar to that of 1 µM
fenoterol under these conditions, indicating that auto- and/or
heteroreceptor-mediated counterregulation is indeed involved.
The facilitation of NE overflow by increasing concentrations of
fenoterol was most prominent at the shortest preincubation time;
particularly with a 15-min preincubation with 10 and 100 µM
fenoterol, facilitation was diminished compared with that at 1 and 5 min. In the presence of yohimbine and atropine, similar facilitatory
effects of the agonist were observed, although at the highest fenoterol
concentration, some enhancement of the facilitation was observed.
However, the extent of facilitation with 10 and 100 µM fenoterol
(15-min incubation) under auto- and heteroreceptor blockade was clearly
less than that with 1- and 5-min preincubations. These data would
suggest that the
2-adrenoceptors on adrenergic nerve terminals in the guinea pig trachea are readily susceptible to desensitization.
It should be mentioned that exhaustion of endogenous neurotransmitter pools is an unlikely explanation for the time-related effects observed with fenoterol because 1) facilitation of NE release increased with all fenoterol concentrations, being most pronounced at S7 after a 1-min fenoterol preincubation, and 2) repeated atropine incubations result in equal facilitations of ACh release (19; unpublished results).
The observation that prejunctional -adrenoceptors on adrenergic
nerve endings are sensitive to desensitization is not unexpected, although it has not been analyzed as such in the guinea pig trachea. Rapid desensitization of these receptors has been previously
demonstrated in isolated rat kidney preparations, with isoproterenol
producing a bell-shaped concentration-response curve with 20- and 5-min but not with 2-min exposure times (10). Our results do not show a
bell-shaped curve of NE overflow when tracheae are exposed to increasing fenoterol concentrations. This difference in response may be
due to a different receptor density or coupling efficiency on
sympathetic nerve endings in the renal artery compared with that in the
trachea or simply to differences in experimental setup and design.
The observations by Belvisi et al. (4) and Zhang et al. (24) that both
isoproterenol and forskolin facilitate ACh release indicate that the
prejunctional 2-adrenoceptor
signaling, at least in cholinergic nerve endings, is through adenylyl
cyclase and cAMP. Two different protein kinases,
-adrenergic-receptor kinase (
-ARK) and cAMP-dependent protein
kinase A (PKA), are known to be involved in short-term
-adrenoceptor
desensitization.
-ARK has been shown to phosphorylate the
agonist-activated
-adrenoceptor rapidly; as a consequence, another
cytosolic protein,
-arrestin, binds to the phosphorylated receptor
leading to uncoupling from the Gs
protein (see Ref. 3 for a review). In contrast, PKA-mediated phosphorylation of the
-adrenoceptor proceeds at a slower rate (9,
11). Recently, McGraw and Liggett (12) have shown that the
desensitization susceptibility of
-adrenoceptors in different pulmonary cell types is clearly related to cellular levels of
-ARK
rather than of PKA. It is tempting to speculate that the differential
desensitization susceptibilities of the two prejunctional
2-adrenoceptor populations are
related to differences in the involvement of
-ARK, this kinase
having a more prominent role in adrenergic nerve terminals. However,
the differential time frame in which the facilitatory responses develop
and the differential susceptibility to desensitization of the
facilitatory
2-adrenoceptors on
cholinergic and adrenergic nerves may also suggest the involvement of
distinct intracellular signaling pathways.
In conclusion, the results presented in this paper are the first
demonstration that EFS-evoked overflow of both endogenous ACh and NE
from guinea pig trachealis autonomic nerves are augmented by
prejunctional 2-adrenoceptor
activation. The physiological and therapeutic significance of these
facilitatory
2-adrenoceptors is
not completely clear. ACh release appears under dual (epithelium and
nerve) and opposite (inhibition and facilitation) control of
-adrenergic receptors, at least in guinea pig airways (20; present
study). Adrenergic innervation in the human lung is generally believed
to project to the vasculature and glands rather than to airway smooth
muscle. Enhanced NE release from vascular nerves might cause
vasoconstriction, thereby reducing vasocongestion and decreasing the
tendency for edema formation; alternatively, or in addition, NE might
overflow to relax airway smooth muscle, and there may be direct
(although sparse) adrenergic innervation of airway smooth muscle in the
human lung as well (8). Bearing this in mind, it should be noted that,
although the overflow of both the bronchoconstricting neurotransmitter
ACh and the bronchodilating neurotransmitter NE is augmented by
fenoterol, the capacity of prejunctional
2-adrenoceptors on adrenergic
nerves is markedly higher compared with that on cholinergic nerves
after short but also after long incubation periods and both with
and without functional auto- and heteroreceptor counterregulation. As a
result,
2-adrenoceptor agonists
might have indirect bronchodilatory effects, through the enhancement of
NE overflow, in addition to the direct relaxant action on bronchial
smooth muscle that occurs through postjunctional
2-adrenoceptors.
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ACKNOWLEDGEMENTS |
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We thank Frans Brouwer for experimental support. Zeneca Pharmaceuticals (Macclesfield, UK) is acknowledged for the donation of ICI-118551.
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FOOTNOTES |
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This work was supported by Netherlands Asthma Foundation Grant 93.70.
Address for reprint requests: J. R. A. de Haas, Department of Molecular Pharmacology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
Received 27 May 1997; accepted in final form 30 November 1998.
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