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Department of Geriatrics and Department of Pathology, Faculty of Medicine, University of Tokyo, Tokyo 113; and Imperial Household Agency, Tokyo 100, Japan
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
FOOTNOTES
REFERENCES
ABSTRACT 
Nagase, Takahide, Tomoko Aoki, Teruaki Oka, Yoshinosuke
Fukuchi, and Yasuyoshi Ouchi. ET-1-induced bronchoconstriction is
mediated via ETB receptor in mice.
J. Appl. Physiol. 83(1): 46-51, 1997.
Endothelin (ET)-1 is one of the most potent agonists of airway
smooth muscle and can act via two different ET receptor subtypes, i.e.,
ETA and
ETB. To determine the effects of
ET-1 on in vivo pulmonary function and which ET receptors are involved in murine lungs, we investigated 1)
the effects of ET and sarafotoxin S6c (S6c), a selective
ETB agonist, on pulmonary function
and 2) the effects of BQ-123 and
BQ-788, specific ETA- and
ETB-receptor antagonists, on
ET-1-induced bronchoconstriction. ICR mice were anesthetized and mechanically ventilated (frequency = 2.5 Hz, tidal
volume = 8 ml/kg, positive end-expiratory pressure = 3 cmH2O). Intravenous ET-1, ET-2,
and ET-3 increased lung resistance similarly and equipotently, whereas
S6c elicited a greater degree of bronchoconstriction. Mice were then
pretreated with saline (Sal), BQ-123 (0.2, 1, and 5 mg/kg), or BQ-788
(0.2, 1, and 5 mg/kg) before administration of ET-1
(10
7 mol/kg iv). No dose of
BQ-123 blocked ET-1-induced constriction, whereas pretreatment with
each dose of BQ-788 significantly inhibited ET-1-induced responses.
There were significant differences in morphometrically assessed airway
constriction between Sal and BQ-788 and between BQ-123 and BQ-788,
whereas no significant difference was observed between Sal and BQ-123.
There were no significant morphometric differences in the airway wall
area among the three groups. These observations suggest that the
ETB- but not
ETA-receptor subtype may mediate
the changes in murine pulmonary function in response to ET-1. In
addition, the ETB-receptor
antagonist reduces ET-1-induced airway narrowing by affecting airway
smooth muscle contraction in mice.
BQ-123; BQ-788; airway resistance; wild-type mice; endothelin-1; endothelinA receptors; endothelinB receptors
INTRODUCTION ENDOTHELIN (ET)-1 is a 21-amino acid peptide isolated
from vascular endothelial cells (30). ET-1 has been demonstrated to be
one of the most potent agonists of both vascular and airway smooth
muscle in various species, including mice (5, 15, 27, 28, 30). Recent
studies suggest that ET-1 may be involved in the pathogenesis of asthma
(6, 16, 25), pulmonary inflammation (18), and pulmonary vascular
disease (3). ETs act on two different G-protein-coupled
receptors, i.e., ETA and
ETB receptors, which were cloned
from the cDNA library in bovine and rat lungs, respectively (1, 23).
ETA receptors are characterized by the rank order of affinities: ET-1 = ET-2 > ET-3 (1). In contrast, ETB receptors have a similar
affinity for ET-1, ET-2, and ET-3 (23). Recently, species differences
in ET-receptor distributions in lungs have been reported. In guinea
pigs, both ETA and
ETB receptors are involved in
ET-1-induced bronchoconstriction in vivo (19), whereas
ETB receptors mediate ET-1-induced
airway responses in rats in situ (13) and in humans in
vitro (7).
Recently, several types of transgenic mice have been established to
elucidate the roles of the ET ligand-receptor system (8, 12). To
examine the roles of ET in the pathogenesis of various pulmonary
diseases, including asthma, these transgenic mice are expected to be
employed as appropriate animal models. However, even in genetically
wild-type mice, the roles of ET receptors in airway physiology remain
to be clarified.
We hypothesized that ET-1 might affect wild-type murine lung via either
ET-receptor subtype in vivo. To test this hypothesis, we obtained
dose-response curves for ET-1, ET-2, ET-3, and sarafotoxin S6c (S6c), a
selective ETB agonist (29), in ICR
mice. We then investigated the effects of ET-1 on airways of ICR mice
by using ETA- and
ETB-selective antagonists, i.e.,
BQ-123 (22) and BQ-788 (9), respectively. In addition, we questioned
whether and how ET-receptor antagonists would modify ET-1-induced
constriction, i.e., whether the
ETA or
ETB antagonist would affect airway
smooth muscle shortening or airway wall thickening. To answer this
question, we performed morphometric analysis of airways.
MATERIALS AND METHODS
|
9 to
107 mol/kg. In a
preliminary experiment, the administration of
>107 mol/kg ET-1, ET-2,
or ET-3 caused severe arrhythmia or cardiac failure.
After two deep inflations (peak Ptr of 30 cmH2O) were
performed, 0.1 ml of PBS and peptide solutions were given
intravenously in half-log increasing doses to obtain cumulative
dose-response curves (n = 5 for each
group).
Effects of BQ-123 and BQ-788 on ET-1-induced
bronchoconstriction.
Two minutes before the bolus of 0.1 ml of a solution containing
107 mol/kg ET-1, animals
were pretreated with one of the following solutions:
1) saline as controls
(n = 7, Sal group);
2) 0.2, 1, or 5 mg/kg BQ-123
(n = 5, respectively, BQ-123 group);
or 3) 0.2, 1, or 5 mg/kg BQ-788
(n = 5, respectively, BQ-788 group).
Saline was used as the vehicle for BQ-123, whereas BQ-788 was dissolved in 1% polyoxyethylene hydrogenated castor oil (HCO 60; Nikko
Chemicals, Tokyo, Japan) in saline (9). After the pretreatment of each solution, we made a measurement as baseline. After the bolus of 107 mol/kg ET-1,
measurements were made at intervals up to 7 min.
Morphometric study.
In groups pretreated with Sal, BQ-123 (5 mg/kg), and BQ-788 (5 mg/kg)
(n = 4 for each group), we studied the
ET-1-induced responses by using morphometric techniques. During
ET-1-induced responses (5 min after ET-1 administration), the lungs
were removed intact and frozen with liquid nitrogen. By delivering a
constant flow into the trachea, we maintained a constant Ptr of 3 cmH2O during
freezing. Frozen lungs were fixed in Carnoy solution
(60% ethyl alcohol, 30% chloroform, and 10% acetic acid) at
70°C for 18 h. Progressively increasing concentrations of
ethanol at 20°C were then substituted for the Carnoy
solution until 100% ethanol was reached. The tissue was maintained at
20°C for 4 h, warmed to 4°C for 12 h, and then allowed
to reach and remain at room temperature for 2 h. After fixation, the
tissue blocks obtained from midsagittal slices of the lungs were
embedded in paraffin. Blocks were cut 4-µm thick by using a
microtome. Slides were stained with hematoxylin and eosin. We assessed
tissue shrinkage, and subsequent measurements were corrected for
shrinkage.
We assessed airway constriction by measuring the length of the
epithelial basement membrane (Pbm) and the area
(Abm) it
circumscribed by projecting microscopic images onto a digitizer by
means of a drawing attachment fixed to the microscope. The ideal area
of the lumen of the relaxed airway
(Abm*)
was then calculated as
|
RESULTS
Effects of BQ-123 and BQ-788 on ET-1-induced bronchoconstriction. Figure 2 demonstrates a representative time course of the reponses to ET-1 bolus administration in mice. ET-1 provoked a sustained increase in RL and elicited a maximal response 3-5 min after bolus administration, suggesting induced bronchoconstriction without initial bronchodilation in vivo.
7 mol/kg ET-1 in mice.
Lung resistance demonstrated sustained increases after ET-1
administration. BAS, baseline.
Figure 3 summarizes the responses to ET-1 in each experimental group. There were no significant differences in baseline RL values among each group. In the saline-pretreated group, 10
7 mol/kg ET-1 caused
increases in RL from 0.415 ± 0.035 to 1.320 ± 0.124 cmH2O · ml1 · s.
As shown in Fig. 3, no dose of BQ-123 blocked ET-1-induced constriction. In a marked contrast, pretreatment with >0.2 mg/kg BQ-788 significantly inhibited ET-1-induced constriction.
7 mol/kg) induced
responses in mice. RL, lung
resistance. * P < 0.01 vs.
Sal-pretreated group.
Morphometric study. Table 1 and Fig. 4 summarize the morphometric data. There were no significant differences in Pbm or D2/D1 among the Sal, BQ-123, and BQ-788 groups. These results indicate that there were no significant biases among the three groups in terms of airway selection. There were significant differences in Abm/Abm* between Sal and BQ-788 and between BQ-123 and BQ-788 (P < 0.001), whereas no significant difference in Abm/Abm* was observed between Sal and BQ-123 (Fig. 4). There were no significant differences in WA/Abm* among the three groups.
|
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7 mol/kg) induced
bronchoconstriction in mice (n = 4 for
each group). Abm*,
ideally relaxed area;
Abm/Abm*,
degree of airway constriction.
* P < 0.01 vs. Sal- and
BQ-123-pretreated groups.
Photomicrographs of representative airways from Sal, BQ-123, and BQ-788 groups (Fig. 5) show substantial airway narrowing in the Sal and BQ-123 groups. On the other hand, airway narrowing is minimal in the BQ-788 group.
DISCUSSION
The results of the present experiments show that ET-1, ET-2, and ET-3 are equipotent as bronchoconstrictor agonists and that S6c, a specific ETB agonist, is more potent than ETs. BQ-788, but not BQ-123, reduces the bronchial responses to ET-1 in mice in vivo. Morphometric results demonstrate that BQ-788 reduces ET-1-induced airway narrowing by affecting airway smooth muscle contraction but not airway wall thickening. These findings suggest that the ETB- but not ETA-receptor subtype may have important physiological roles in airways in mice in vivo.
Several technical issues warrant consideration before discussion of the results. It has been demonstrated that airway resistance is lung-volume dependent even after induced constriction (14, 20, 21). Therefore, to compare airway resistance before and after constriction, it is important to be sure that lung volumes are similar under all experimental conditions. In the present experiment, we maintained PEEP at 3 cmH2O for all experimental groups. To make comparisons of functional and structural measures, it is also important that lung volume is maintained at the same level during freezing as during the physiological measurements. Therefore, we delivered constant flow into the trachea during freezing, maintaining Ptr equal to 3 cmH2O. Potentially, artifacts could arise during the freezing process, which was very rapid (26), much faster than the time constant of relaxation after constriction induced by intravenous administration of ET-1. Although constriction might have exaggerated any freezing artifact, no topographic or systematic distribution of atelectasis was observed among the groups.
Dose-response curves for ET-1, ET-2, and ET-3 indicate that these three ETs are equipotent as bronchoconstrictor agonists. S6c, a specific ETB agonist, induced a greater degree of bronchoconstriction and was more potent than ETs. Based on the observations that the ETB receptor is nonisopeptide selective (23), this rank order of potency (S6c > ET-1 = ET-2 = ET-3) suggests that the bronchoconstrictor action of ETs is mediated via the ETB receptor in mice in vivo.
In ICR mice, BQ-123 did not block ET-1-induced constriction. In contrast, pretreatment with BQ-788 significantly inhibited ET-1-induced constriction. These data suggest that ET-1-induced contraction is an ETB-mediated response. White et al. (28) have reported that in guinea pigs ET-1-induced airway contraction is potentially mediated through the release of products of cyclooxygenase from the epithelium. The present observations in ICR mice may be explained by the possible mechanism that the ETB receptor may reside on the epithelium of the airways and that the ETB-receptor antagonist BQ-788 may inhibit ET-1-induced bronchoconstriction by blocking the activation of cyclooxygenase in the epithelium.
The present observations in mice are somewhat different from the previous studies in other species. In pigs, blood vessels and bronchi are rich in the ETA receptor, and lung parenchyma is rich in the ETB receptor (22). In guinea pigs, both ETA and ETB receptors are involved in ET-1-induced bronchoconstriction in vivo (19), whereas differences in the relative distribution of ET-receptor subtypes exist between trachea (ETA) and bronchus (ETB) in vitro (7). On the other hand, in rats in situ (13) and in humans in vitro (4, 7), ETB receptor may play an important role in ET-1-elicited bronchoconstriction, compatible with the present findings in mice in vivo. In human bronchial smooth muscle, it has been reported by Goldie et al. (4) that ~82-88% of ET-1 binding sites are ETB receptors.
Indexes of airway constriction (Abm/Abm*) and WA thickening (WA/Abm*) were calculated to assess airway narrowing and WA edema formation. There were significant differences in the degree of airway constriction between Sal and BQ-788 and between BQ-123 and BQ-788 groups, whereas no significant difference was observed between Sal and BQ-123 groups. There were no significant differences in the WA among the three groups. These results suggest that antagonism of ETB attenuates ET-1-induced airway narrowing by affecting airway smooth muscle contraction.
Recently, the pathophysiological importance of ET-1 has been reported in experiments using transgenic mice. Kurihara et al. (12) have disrupted the mouse Edn-1 locus encoding ET-1 and observed that resultant mice homozygous for ET-1 null mutation represent morphological abnormalities of the pharyngeal arch-derived craniofacial tissues and organs, indicating that ET-1 is essential to normal embryonic development. They have also reported (11) that ET-1 knockout homozygous mice display cardiovascular malformations, including aortic arch malformations and ventricular septal defect, and that the frequency and extent of these abnormalities are increased by antagonism of ETA receptor by using BQ-123. It has also been demonstrated (8) that a targeted disruption of the mouse ETB-receptor gene results in aganglionic megacolon and pigmentary disorders resembling human Hirschsprung's disease.
The present observations in genetically wild-type mice may provide useful information to study the roles of ET ligand-receptor systems in murine airway biology. To investigate the roles of ETs in the pathogenesis of ET-related diseases, including bronchial asthma, transgenic mice such as ET-1 knockout mice (12) could be employed as animal models in future studies. In such studies, it is essential to understand the basic roles of ET ligands and receptors in genetically wild-type mice. In addition, in both humans and mice, ETB-receptor subtypes have crucial roles in ET-1-induced airway responses (4, 7). This resemblance between humans and mice may suggest that mice are one of the most appropriate animal models for study of the roles of ET-1 in the etiology of bronchial asthma.
In conclusion, the order of bronchoconstrictive potency was S6c > ET-1 = ET-2 = ET-3 in mice in vivo. Only BQ-788 reduced the pulmonary responses to ET-1 in ICR mice. BQ-788 reduced ET-1-induced airway narrowing, although it did not affect WA thickening. These observations suggest that the ETB- but not ETAreceptor subtype may have important roles in airway physiology in ICR mice, one of the most common wild-type murine species.
FOOTNOTES
Address for reprint requests: T. Nagase, Dept. of Geriatrics, Faculty of Medicine, Univ. of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan.
Received 10 October 1996; accepted in final form 4 March 1997.
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