Br. J. Pharmacol (1994), 113, 508-5 12
(D Macmillan Press Ltd,
1994
Role of kinins in anaphylactic-induced bronchoconstriction
mediated by tachykinins in guinea-pigs
Fabio L.M. Ricciardolo, *tJay A. Nadel, Paul D. Graf, 2Claude Bertrand, Shigemi Yoshihara
& 'Pierangelo Geppetti
Cardiovascular Research Institute and the Departments of *Medicine and tPhysiology, University of California San Francisco,
California, U.S.A.
1
In the present study,
we
have investigated the role of kinins in allergen-induced bronchoconstric-
tion.
2 Anaesthetized guinea-pigs were sensitized to ovalbumin, ventilated artificially, pretreated with
atropine (1.4 imol kg-', i.v.) and total pulmonary resistance (RL) measured. In preliminary studies in
the presence of the neutral endopeptidase inhibitor, phosphoramidon (4.5 pmol kg-', i.v.), the
bradykinin B2 receptor antagonist Hoe 140 (0.1 iimol kg-', i.v.) completely abolished the increase in RL
following aerosolized bradykinin (1 mM, 40 breaths), but had no effect on the increase in RL following
aerosolized neurokinin A (NKA, 10 JiM, 40 breaths). On the other hand, a combination of the NK,
(CP-96,345, 2 pmol kg-', i.v.) and NK2 (SR 48968, 0.3 gmol kg-', i.v.) tachykinin receptor antagonists
abolished completely the increase in RL produced by NKA and partially inhibited the increase in RL
produced by bradykinin. These results confirm previous studies that suggest that bradykinin induces the
release of tachykinins from sensory nerves in guinea-pig airways.
3 Aerosolized ovalbumin (0.5%, 5 breaths) increased RL in sensitized guinea-pigs pretreated with
atropine (1.4 mmol kg-', i.v.), an effect that began within 2 min and reached a maximum within 5 min;
RL remained above baseline at 20 min. Pretreatment with the bradykinin B2 receptor antagonist, Hoe
140, decreased the bronchoconstrictor effect of ovalbumin markedly at 10 to 20 min. In the presence of
phosphoramidon (4.5 gmol kg-', i.v.) the inhibition induced by Hoe 140 was apparent earlier and
remained over the 20 min period of study.
4 Pretreatment with a combination of NK, (CP-96,345) and NK2 (SR 48968) tachykinin receptor
antagonists also markedly inhibited ovalbumin-induced bronchoconstriction; addition of the bradykinin
B2 receptor antagonist to the NK, and NK2 tachykinin receptor antagonists had no additional inhibitory
effect on antigen-induced bronchoconstriction.
5 These findings confirm that activation of sensory nerves to release tachykinins in guinea-pig airways
contribute to antigen-induced bronchoconstriction, and provide evidence that tachykinin release is due
to kinins generated during the allergic response.
Keywords: Kinins; tachykinins; receptors; neurogenic inflammation; allergen challenge; bronchoconstriction; sensory
Hoe 140; SR 48968; CP-96,345.
nerves;
Introduction
Stimulation of a subpopulation of sensory nerves causes the
release of neuropeptides, including the tachykinins substance
P (SP) and neurokinin A (NKA), from their peripheral terminals. This release produces a series of effects collectively
referred to as 'neurogenic inflammation', which in the airways includes plasma extravasation and bronchconstriction
(Lundberg & Saria, 1983; Lundberg et al., 1984; Barnes,
1986; Nadel, 1991). Plasma extravasation and bronchconstriction are effects produced by exposure to antigen in sensitized animals. Recently, we showed that tachykinins
released from sensory nerve endings (via activation of NK2
and NK, tachykinin receptors) play an important role in
antigen-induced plasma extravasation and bronchoconstriction in sensitized guinea-pigs (Bertrand et al., 1993a,b). As
there is no evidence that the antigen-antibody complex per se
activates sensory nerves, we reasoned that mediators released
from tissue, inflammatory cells or plasma may be involved in
the antigen-evoked stimulation of sensory nerves.
Kinins, including bradykinin, derived from a plasma precursor, and kallidin released from a tissue precursor, have
Author for correspondence at present address: Laboratory of
Clinical Pharmacology and Institute of Internal Medicine IV,
University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
2Present address: Ciba-Geigy A.G., Pulmonary Pharmacology,
Pharma Division, R-1056.2.15, CH-4002, Basel, Switzerland.
been proposed to take part in the allergic inflammatory
response because increased kinin levels have been detected in
immediate and late phase reactions in experimental animals
(Erjefalt et al., 1993) and in man (Christiansen et al., 1992).
Bradykinin antagonists have been found to reduce the late
bronchial response (Abraham et al., 1991) and the hyperresponsiveness (Farmer et al., 1992) that occurs after exposure
to antigen. Bradykinin potently stimulates primary sensory
neurones (Kaufman et al., 1980) and releases neuropeptides
from their peripheral endings in different tissues, including
the airways (Geppetti et al., 1988; Saria et al., 1988; Geppetti, 1993). Kinins released upon exposure to antigen play
an important role in the activation of sensory nerves, which
contribute substantially to the antigen-evoked plasma extravasation in guinea-pigs (Bertrand et al., 1993d).
In the present study, we investigated whether bronchoconstriction in response to antigen and mediated by activation of
sensory nerves is due to release of kinins. To test this
hypothesis, we used Hoe 140, a selective and potent peptide
antagonist of B2 bradykinin receptors (Hock et al., 1991),
because this compound completely prevents the bronchoconstriction evoked by aerosolized or intravenously injected
bradykinin in guinea-pigs (Wirth et al., 1993). The effect of
Hoe 140 on antigen-induced bronchoconstriction was compared to the effect produced by the combination of nonpeptide antagonists of NK2 (SR 48968) (Emonds-Alt et al., 1992)
and NK, (CP-96,345) (Snider et al., 1991) tachykinin recep-
KININS IN ANTIGEN-INDUCED BRONCHOCONSTRICTION
tors. The combination of NKI and NK2 tachykinin receptor
antagonists was used because this combination is necessary
to block completely the bronchoconstriction induced by
tachykinins released by capsaicin in guinea-pigs in vivo (Bertrand et al., 1993c). Some experiments were performed in
animals pretreated with phosphoramidon, because previous
studies (Bertrand et al., 1993a,b) showed that blockade of
neutral endopeptidase (NEP) activity by phosphoramidon
increases the sensory nerve-mediated responses to antigen.
Methods
Animals
Male Hartley guinea-pigs (Simonsen Laboratories Inc., Gilroy, CA, U.S.A) that weighed 250-300 g at the time of
housing, were used in this study. They were kept in a
temperature-controlled environment with standard laboratory
food and water freely available.
Sensitization procedure
Animals were sensitized according to a protocol described
previously (Dunn et al., 1988; Bertrand et al., 1993a). Sensitization consisted of two separate injections of 70 mg ovalbumin (Grade V) in 1.5 ml 0.9% NaCl intraperitoneally, with
an interval of one week between the injections. The animals
were studied two weeks after the second injection. Nonsensitized (control) animals were injected twice with 1.5 ml
0.9% NaCl.
Measurement of total pulmonary resistance (RL)
Animals were anaesthetized using sodium pentobarbitone
(45 mg kg-', i.p.; Anthony Product Corp., Arcadia, CA,
U.S.A.) and then ventilated artificially with a tracheal cannula, using a constant-volume ventilator (model 683; Harvard Apparatus Co., Inc., South Natick, MA, U.S.A.) at a
frequency of 80 breaths min-'. The tidal volume was
adjusted to maintain normal arterial blood gases as described
previously (Dusser et al., 1988). Airflow was monitored continuously with a pneumotachograph (A. Fleisch, Medical
Inc., Richmond, VA, U.S.A.) connected to a differential
pressure transducer (model DP45; Validyne Engineering
Corp., Northrige, CA, U.S.A.). A fluid-filled polyethylene
catheter was introduced into the oesophagus to measure the
oesophageal pressure as an approximation of pleural pressure. Intratracheal pressure was measured with a polyethylene catheter inserted into a short tube connecting the
tracheal cannula to the pneumotachograph. The transpulmonary pressure (defined as the pressure difference between
the intratracheal and oesophageal pressures) was measured
with a differential pressure transducer (model DP7; Validyne
Engineering Corp.). Output signals representing transpulmonary pressure and airflow were amplified with an amplifier
(model CD19; Validyne Engineering Corp.) and recorded on
a polygraph recorder (model 1508 B Visicorder; Honeywell,
Inc., Denver, CO, U.S.A.). RL was calculated as described
previously (Dusser et al., 1988). The right jugular vein and
the left carotid artery were cannulated to permit administration of drugs and to withdraw a sample of blood for arterial
blood gas measurement.
Experimental design
Baseline RL remained stable for at least 2 h, and no significant changes were produced by aerosols (5 breaths or 40
breaths) or i.v. injection (1 ml kg-') of 0.9% NaCl after a
stabilization period of 30 min. Aerosols of saline or antigen
(ovalbumin 0.5%; 5 breaths) were generated by an ultrasonic
nebulizer (model 25, DeVilbiss, Somerset, PA) and were
delivered into the airways by the respirator via the tracheal
509
cannula (aerosol delivery rate, 0.2 ml min- 1). All animals
were pretreated with atropine (1.4 ,mol kg-', i.v., 15 min
before the stimulus). Phosphoramidon (4.5 pmol kg- , i.v.)
was given 5 min before the stimulus.
Drugs
Ovalbumin, atropine and histamine were obtained from
Sigma Chemical (St. Louis, MO, U.S.A.). Phosphoramidon,
bradykinin and NKA were purchased from Peninsula Laboratories, Inc. (Belmont, CA, U.S.A.). CP-96,345 ((2S,3S) cis2-(diphenylmethyl)-N-((2-methoxy-phenyl)-methyl)- 1 -azabicyclo[2.2.2]octan-3-amine) and SR 48968 (S)-N-methyl-N([4-
(-acetyl-amino4-phenylpiperidino)-2-(3,4dichlorophenylbutyl]
benzamide) were kindly provided by Dr J.A. Lowe III (Pfizer
Inc, Groton, CT, U.S.A.) and Dr X. Emonds-Alt (Sanofi
Recherche, Montpellier, France), respectively. Hoe 140 (DArg-[Hyp3,This5,D-Tic7,Oic8]-bradykinin) was a kind gift of
Dr F.J. Hock (Hoechst AG, Frankfurt, Germany). Drugs
were dissolved in 0.9% saline or in dimethyl sulphoxide (Hoe
140 and SR 48.968). Further dilutions were made in 0.9%
saline.
Statistical analysis
Values in the text and figures arpe the mean ± standard error
of the mean (s.e.mean). Statistical comparisons were performed by a one way analysis of variance and Dunnett's test
or bilateral unpaired Student' t test, when appropriate. In all
cases, a P value of less than 0.05 was considered significant.
Results
Aerosolized bradykinin (I mM, 40 breaths) increased RL approximately 2 fold above baseline value, and the bradykinin
B2 receptor antagonist Hoe 140 (0.1 1tmol kg-', i.v., 15 min
before the stimulus) abolished the bronchoconstriction completely (Figure lb) in guinea-pig pretreated with atropine
(1.4 pmol kg- ') and phosphoramidon (4.5 pmol kg-'). A
combination of NK2 (SR 48968, 0.3 pmol kg-", i.v., 15 min
before the stimulus) and NKI (CP-96,345, 2 Imol kg-I i.V.,
5 min before the stimulus) tachykinin receptor antagonists
decreased the bradykinin-induced increase in RL by approximately 60% (Figure lb). Aerosolized NKA (10 pLM, 40
breaths) increased RL more than 3 fold above baseline value,
an effect that was not changed by pretreatment with Hoe 140
(0. Itmol kg-', i.v.), but was abolished completely by the
combination of NK2 (SR 48968, 0.3 tmol kg-' i.v.) and NK,
(CP-96,345, 2 jimol kg-' i.v.) tachykinin antagonists (Figure
la).
Aerosols of the vehicle of ovalbumin (0.9% NaCl, 5
breaths) did not increase RL significantly over the 20min
period of study in guinea-pigs sensitized to ovalbumin (data
not shown). However, aerosolized ovalbumin (0.5%, 5
breaths) increased RL approximately 2 fold above baseline
value in the sensitized guinea-pigs: the increase in RL was
evident within 2 min after exposure, reached a maximum
within 5 min, and RL was still increased above baseline after
20 min (Figure 2a). Pretreatment with the bradykinin B2
receptor antagonist Hoe 140 (0.1 limol kg-", i.v.) decreased
the bronchoconstrictor effect of aerosolized ovalbumin at 10,
15 and 20 min after the delivery of ovalbumin. When the
guinea-pigs were pretreated with phosphoramidon (4.5 jtmol
kg-', i.v.), a selective inhibitor of NEP, the increase in RL
after inhalation of ovalbumin was not significantly greater
than the increase obtained in the absence of phosphoramidon
(Figure 2a,b). In the presence of phosphoramidon Hoe 140
still decreased markedly the ovalbumin-induced increase in
RL (Figure 2b): a significant inhibition by Hoe 140 of the
ovalbumin-induced bronchoconstriction was found as early
as 3 min and remained at 20 min (Figure 2b).
F.L.M. RICCIARDOLO et al.
510
Neurokinin A
a
0.8
0.6
T
In another series of experiments in the presence of phosphoramidon, we studied the effect of adding Hoe 140 to the
tachykinin receptor antagonists SR 48968 (0.3 pmol kg-',
i.v.) and CP-96,345 (2 jimol kg-', i.v.): the increase in RL
produced by aerosolized ovalbumin was decreased significantly by pretreatment with the combination of SR 48968
and CP-96,345 (Figure 3). In animals whose pretreatment
included SR 48968 and CP-96,345 plus Hoe 140, no further
reduction in the ovalbumin-induced effects occurred compared to the inhibitory effects of the NK2 and NKI
tachykinin antagonists alone (Figure 3).
T
-
0.4 -
0.2
T
-
Discussion
i)
E
0-
I
0
0.8
E
The major finding in the present study is that a selective
bradykinin B2 receptor antagonist decreases markedly oval-
b
Bradykinin
1.0 -
.-
T
0.6 -
*
0.8
I
0.4 -
E 0.6
C4
0
E 0.4-
0.2 -
0
0.2
0o
Hoe 140
Baseline
SR 48968
CP-96,345
0
10
20
15
Time (min)
Figure 3 Effect of the combination of antagonists on NK2 (SR
48968, 0.3gmolkg-', i.v., 15min before stimulus) and NK, (CP96,345, 2 inmol kg-', i.v., 5 min before stimulus) tachykinin receptor
(@) or the combination of these two antagonists plus the bradykinin
B2 receptor antagonist, Hoe 140 (0.1 pmol kg-', i.v., 15 min before
stimulus) (0), on the increase in total pulmonary resistance (RL)
evoked by aerosolized ovalbumin (0.5%, 5 breaths) in sensitized
guinea-pigs. Anaesthetized animals were pretreated with atropine
(1.4 pmol kg-', i.v., 15min before stimulus) and phosphoramidon
(4.5 pmol kg-', i.v., 5 min before stimulus). Controls (0) received
the vehicle of Hoe 140 and SR 48968 (10% dimethyl sulphoxide in
0.9% saline) 15 min before the stimulus. Each point is the
mean ± s.e.mean of 7 experiments. *P<0.05 versus control.
0
Figure 1 Effect of the bradykinin B2 receptor antagonist (Hoe 140;
0.1 Amol kg-', i.v., given 15 min before the stimulus) (hatched column), or the combination of tachykinin NK2 (SR 48968;
0.3 9mol kg-', i.v., given 15 min before stimulus) and NK1 (CP96,345; 2 gmol kg-', i.v., given 5 min before stimulus) receptor
antagonists (cross-hatched column) on the maximal increase in total
pulmonary resistance (RL evoked) by aerosolized bradykinin (b) or
aerosolized neurokinin A (a). Animals were pretreated with phosphoramidon (4.5 pmol kg-', i.v., given 5 min before stimulus) and
atropine (1.4 pmol kg-', i.v., given 15 min before stimulus). Vehicle
(filled columns) indicates animals pretreated with the vehicle of Hoe
140 and SR 48968 (10% dimethyl sulphoxide in 0.9% saline) 15 min
before the stimulus. Baseline (open columns) indicates values
measured before the beginning of the aerosolization of the stimulus.
Each column is the mean ± s.e.mean of at least 5 experiments.
*P <0.01 versus control.
b
a
1.0
5
-
0.8 w
E
0.6 *
0
I
E
C-.
0.4 -
Jc
0.2 00
5
10
15
20
5
10
15
20
Time (min)
Time (min)
Figure 2 Effect of Hoe 140 (0.1 jsmol kg-', i.v., 15 min before the stimulus) (@) and its vehicle (10% dimethyl sulphoxide in 0.9%
saline) (0) on the increase in total pulmonary resistance (RL) evoked by aerosolized ovalbumin (0.5%, 5 breaths) in sensitized
guinea-pigs. Experiments were performed in the absence (a) or in the presence of phosphoramidon (4.5 ymol kg-', i.v., 5 min
before stimulus) (b). Each point is the mean ± s.e.mean of 8 experiments. *P<0.05 vs. Hoe 140.
KININS IN ANTIGEN-INDUCED BRONCHOCONSTRICTION
bumin-induced bronchoconstriction in sensitized guinea-pigs,
thus implicating kinins in this allergic response. Present and
previous (Wirth et al., 1993) findings show that B2 bradykinin receptors mediate bradykinin-induced bronchoconstriction in guinea-pigs. Bradykinin is known to be released into
bronchoalveolar lavage fluid in both sensitized guinea-pigs
(Erjefalt et al., 1993) and in asthmatic human subjects (Christiansen et al., 1992) after inhalation of antigen, adding
credibility to the present finding that a bradykinin B2
antagonist inhibits antigen-induced bronchoconstriction to a
considerable extent.
The present studies also provide data on the importance of
tachykinins in the antigen-induced bronchoconstriction in
guinea-pigs. These results, which confirm previous findings
(Bertrand et al., 1993b), indicate that a combination of NKI
and NK2 receptor antagonists inhibit considerably antigeninduced bronchoconstriction in sensitized guinea-pigs. Furthermore, present results provide evidence that kinins
released into airways as a result of antigen-antibody interactions and the subsequent release of tachykinins from the
sensory nerves in the airways acts as a 'cascade' to produce
allergic bronchoconstriction. This conclusion is based on the
following: first, bradykinin is known to stimulate sensory
nerves and to release sensory neuropeptides from several
tissues, including airways (Geppetti, 1993). When bradykinin
is applied topically to the airways, most of its effects are
mediated by the stimulation of sensory nerves with the subsequent release of tachykinins. In the present studies, bradykinin-induced bronchoconstriction was markedly attenuated
by pretreatment with NKI and NK2 receptor antagonists,
confirming previous studies in which capsaicin pretreatment
was used to deplete tachykinins from sensory nerves (Ichinose et al., 1990). Second, in the present study, pretreatment
with a combination of NKI and NK2 receptor antagonists
markedly reduced antigen-induced bronchoconstriction. Furthermore, addition of a bradykinin B2 receptor antagonist to
the tachykinin antagonists did not further reduce antigeninduced bronchoconstriction.
From these results, we suggest the following sequence of
events: the antigen-antibody response in airways causes the
release of mediators, including kinins. The kinins activate
sensory nerves to release tachykinins which act on their
receptors on airway smooth muscle. Of course, one might
511
hypothesize that the opposite sequence occurs (i.e., that
antigen-antibody interactions in airways cause sensory nerves
to release tachykinins, with the subsequent release of kinins).
Several pieces of information mitigate against this sequence:
first, to our knowledge, tachykinins are not reported to
release kinins in any tissue. Second, in the present study,
tachykinin (NKA)-induced bronchoconstriction was not
inhibited by pretreatment with a bradykinin B2 receptor
antagonist.
Ovalbumin also increases vascular permeability in airways
in sensitized guinea-pigs, and a similar cascade of antigenantibody interaction is hypothesized leading to kinin activation in airways, which in turn causes the release of
tachykinins from sensory nerves, which act on receptors in
the postcapillary venules to increase vascular permeability
(Bertrand et al., 1993d). Thus, in guinea-pigs, similar cascades involving kinin activation and tachykinin release
appear to play a role in both antigen-induced airway smooth
muscle contraction and plasma extravasation.
We showed previously that phosphoramidon, an NEP inhibitor, potentiates the mild bronchoconstriction induced by an
aerosol of 0.1% ovalbumin, but not the marked response
induced by a higher dose of ovalbumin (0.5%) (Bertrand et
al., 1993b). The present results showing that bronchoconstriction induced by 0.5% ovalbumin was not increased by
blockade of NEP are in agreement with these previous data.
However, NEP appears to be involved in the break down of
kinins and/or tachykinins which are released after the inhalation of 0.5% ovalbumin and which mediate the bronchoconstriction in response to this dose of antigen. This conclusion
is suggested by the observation that inhibition of ovalbumininduced bronchoconstriction by Hoe 140 is evident earlier in
animals pretreated with phosphoramidon than in animals not
pretreated with phosphoramidon.
If the present mechanisms found in guinea-pigs also exist
in human subjects, we suggest that bradykinins and/or
tachykinin receptor antagonists may be of value in reducing
symptoms in allergic states where kinins and tachykinins
appear to be involved in the pathophysiological responses.
Supported in part by Program Project HL-24136 from the National
Institute of Health.
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(Received February 7, 1994
Revised May 9, 1994
Accepted June 1, 1994