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Am. J. Respir. Crit. Care Med., Volume 158, Number 1, July 1998, 42-48

Involvement of Tachykinin NK3 Receptors in Citric Acid-induced Cough and Bronchial Responses in Guinea Pigs

SAMIRA DAOUI, CÉCILE COGNON, EMMANUEL NALINE, XAVIER EMONDS-ALT, and CHARLES ADVENIER

Laboratoire de Pharmacologie, Faculté de Médecine Paris-Ouest, 15 rue de l'Ecole de Médecine, 75006 Paris; and Sanofi Recherche, 371 avenue du Pr Blayac, 34184 Montpellier Cedex, France

    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Aerosolized citric acid induces several pulmonary effects including bronchoconstriction, airway inflammation, and cough. Evidence from the use of tachykinin NK1 and NK2 receptor antagonists, as well as chronic treatment with high doses of capsaicin, have suggested that these effects are mediated through the release of tachykinins from sensory nerve endings. In the present study, we have investigated the effects of a tachykinin NK3 receptor antagonist, SR 142801 (osanetant), on cough, bronchoconstriction, and bronchial hyperresponsiveness induced by aerosolized citric acid (0.4 M) in guinea pigs. SR 142801, at 0.3 and 1 mg · kg-1 by intraperitoneal route, significantly inhibited cough in conscious guinea pigs by 57 ± 3 and 62 ± 10% (n = 8), respectively. In anaesthetized guinea pigs, it failed to inhibit the bronchoconstriction induced by citric acid when given alone but abolished it when combined with the tachykinin NK2 receptor antagonist, SR 48968 (saredutant). In guinea pigs pretreated with thiorphan (1 mg · kg-1), aerosolized citric acid (0.4 M, 1 h) induced airway hyperresponsiveness 24 h later, displayed by an exaggerated response to the bronchoconstrictor effect of acetylcholine. A microvascular leakage hypersensitivity also occurred and was demonstrated by a potentiation of the plasma protein extravasation from bronchial vessels induced by histamine. When given once intraperitoneally at 1 mg · kg-1 30 min before the citric acid exposure, SR 142801 inhibited both hyperresponsiveness to acetylcholine and the potentiation of histamine-induced increase in microvascular permeability. The results suggest that tachykinin NK3 receptors are involved in citric acid-induced effects on airways.

    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Sensory nerves have both afferent and efferent functions and, in the airways, their activation may result in a variety of inflammatory and reflex effects such as bronchoconstriction, plasma extravasation, mucus secretion, and cough (1). These effects have been attributed to tachykinins released from the terminals of these activated sensory neurones. Tachykinins are a group of related neuropeptides including substance P, neurokinin A, and neurokinin B, which preferentially interact with the tachykinin NK1, NK2, and NK3 receptors, respectively (4).

Much attention has been focused on the excitatory effects of protons on sensory nerves. Acidic solutions stimulate cutaneous, corneal, and visceral afferents and evoke the release of spinal and/or peripheral tachykinins (5). Among acidic agents, citric acid is an interesting tool and has been extensively used to investigate sensory nerve activation in airways. When inhaled, citric acid causes bronchoconstriction (11), nasal irritation (11), cough (14), bronchial hyperresponsiveness to acetylcholine (18), and hypersensitivity to histamine-induced microvascular leakage (19). The involvement of tachykinin release in the citric acid effects has been demonstrated at first with capsaicin, the pungent extract of red pepper, which is known to provoke at high doses the tachykinin release and also the degeneration of tachykinin-containing sensory nerves (16, 18). Afterwards, this has been confirmed by using tachykinin receptor antagonists. A tachykinin NK2 receptor antagonist, SR 48968 (saredutant), inhibits citric acid-induced bronchoconstriction (12, 13), cough (13, 20, 21) and bronchial hyperresponsiveness to acetylcholine (18). On the other hand, a tachykinin NK1 receptor antagonist, FK 888, inhibits citric acid-induced cough (13), whereas another compound, SR 140333 (nolpitantium), inhibits the exaggerated histamine-mediated microvascular leakage induced by citric acid (19). These studies also showed that at least the tachykinin NK1 and NK2 receptors are directly implicated in citric acid-induced effects on airways.

The aim of the present study was to examine if the tachykinin NK3 receptor may be also involved in citric acid-induced bronchopulmonary effects by using a selective tachykinin NK3 receptor antagonist, SR 142801 (osanetant) (23).

    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Bronchoconstriction

Tricolored guinea pigs (300-400 g) of both sexes were used. They were anesthetized with urethane (1.25 g · kg-1, intraperitoneally). The left jugular vein was cannulated for injection of tachykinin receptor antagonists. A tracheal cannula was inserted and artificial ventilation was maintained with a constant volume ventilator (Model 7025; Ugo Basile, Comerio-Varese, Italy). Animals were ventilated with room air at a rate of 60 breaths per min and at a tidal volume of approximately 10 ml · kg-1. Body temperature was controlled with a heating control device (homeothermic blanket system; Harvard Apparatus Ltd, Kent, UK) and kept at 37° C.

Airway function was assessed by measuring changes in pleural pressure, which can be regarded as an indicator of airway resistance at least in guinea pigs (30). Pleural pressure was determined with a catheter fitted with a 16-gauge needle inserted into the 6th or 7th intercostal space and connected to a pressure transducer (P23XL; Viggo-Spectramed, Bilthoven, The Netherlands). After a 30-min resting period, artificial ventilation was stopped and the tracheal cannula was connected in spontaneously breathing animals directly to a DeVilbiss nebulizer (aerodynamic mean mass, median particle diameter of 0.5- 5 µm, NEB 99; DeVilbiss, Somerset, PA). Aerosol of citric acid solution (0.4 M) was administered for 2 min, and about 0.3 ml of the solution was nebulized per min. After the pleural pressure was returned to baseline or stabilized, artificial ventilation was set running again. The pleural pressure increase was evaluated as the difference (in cm H2O) between the baseline value and the maximum response (peak value) after citric acid aerosol exposure. Mean increase in pleural pressure after the first administration of citric acid aerosol was 7.71 ± 0.40 cm H2O (n = 48). Preliminary experiments have shown that responses to citric acid were reproducible at least three times at 30-min intervals, the second and third responses being 97 ± 2% and 99 ± 3% (n = 6) of the first response, respectively. This citric acid-induced bronchoconstriction was not significantly modified by a pretreatment with atropine (1 mg · kg-1 intraperitoneally), responses being 91 ± 5% of the responses without atropine (n = 4). Tachykinin receptor antagonists were administered alone or in combination 30 min before an aerosol challenge with citric acid.

Cough

Tricolored conscious male or female guinea pigs (300-400 g) were placed in a transparent perspex box, 20 × 10 × 10 cm, that allowed free movement. Changes in pressure induced by respiration and coughing were recorded by a transducer (P23XL; Viggo-Spectramed, Bilthoven, The Netherlands) connected to the box above the air entry port. Pressure changes were amplified (Buxco Electronics, New York, NY) and recorded onto a moving pen recorder (Linseis, GmbH, Selb, Germany). Cough sounds were amplified by a microphone placed in the box. Cough was induced by aerosolized citric acid solution (0.4 M) administered for 10 min with an ultrasonic nebulizer connected to the airflow port. Coughs were counted by a trained observer and recognized by the characteristic animal posture, the sound produced, and the pressure transducer recordings. Coughs were readily distinguished from sneezes.

All studies were carried out at the same time of day. For each experiment, a control number of coughs for 10 min was counted for each animal. After 48 h, animals were treated with saline or SR 142801 (0.1-1 mg · kg-1, intraperitoneally) and the cough number was determined after 30 min.

Airway Hyperresponsiveness to Acetylcholine and Histamine-induced Microvascular Leakage

Exposure to citric acid aerosol. Tricolored unanesthetized, unrestrained male or female guinea pigs (300-400 g) were treated by intraperitoneally administered thiorphan (1 mg · kg-1). Thirty minutes later, they were placed in a Plexiglas chamber (30 × 25 × 15 cm) and exposed for 60 min to an aerosol of citric acid solution (0.4 M) or vehicle solution with an ultrasonic nebulizer. They were continuously watched by a trained observer. They received a single intraperitoneally administered dose (0.1, 0.3, or 1 mg · kg-1) of the tachykinin receptor antagonists or vehicle 30 min before exposure to citric acid aerosol. Twenty-four hours after the citric acid exposure, guinea pigs were anesthetized by urethane (1.25 g · kg-1, intraperitoneally). A jugular vein was cannulated to allow the administration of acetylcholine, histamine, or Evans blue dye. For the measurement of bronchopulmonary reactivity, the animals were also intubated with an endotracheal cannula and artificially ventilated.

Assessment of the in vivo bronchopulmonary reactivity. In a first series of experiments, pulmonary inflation pressure (PIP) was measured using a pressure transducer (P23XL; Viggo-Spectramed) connected to the tracheal cannula via a side-arm and recorded with a recording microdynamometer (Model 7050; Ugo Basile, Comerio-Varese, Italy). The tidal volume (approximately 10 ml · kg-1) was adjusted to give a baseline inflation pressure of 8-10 cm H2O at the end of the inspiration. After a stabilization period of 10 min, acetylcholine was administered at increasing doses (10, 20, 50, 100, 200, and 500 µg · kg-1), 5-10 min apart. Bronchopulmonary responses were expressed as percent response changes versus acetylcholine at 500 µg · kg-1. Acetylcholine (500 µg · kg-1) responses were expressed in cm H2O.

Measurement of airway microvascular leakage. In another set of experiments, vascular permeability was quantified by the extravasation of Evans blue dye (31). Evans blue dye (30 mg · kg-1) was injected followed 1 min later by saline (1 ml · kg-1) or histamine (30 µg · kg-1). The thorax was opened 5 min later, and a blunt-ended, 14-gauge needle passed through a left ventriculotomy into the aorta. The ventricles were cross-clamped, and blood was expelled through an incision in the right atrium at 80 mm Hg pressure with about 100 ml saline (pH 5.5), in order to remove the intravascular dye from the systemic and pulmonary circulation. The lungs were then removed. The connective tissues, vasculature, and parenchyma were gently scraped and the airways were divided into two components: lower part of trachea and main bronchi. The tissues were blotted dry and weighted. Their dye content was extracted in formamide at 37° C for 18 h. Dye concentration was photometrically quantified. Plasma extravasation was expressed as ng dye per mg wet-weight tissue. The dose of histamine (30 µg · kg-1) was chosen from preliminary experiments and gave 30-70% of maximal effect (32).

Statistical Analysis of Results

Data are expressed as means ± SEM. The EC30 value is the dose that provokes a response of 30% of the maximal effect. Statistical analysis of the results was assessed by analysis of variance (ANOVA) followed by Fisher's test. Probability values of p < 0.05 were considered significant.

Drugs

The substances used were citric acid, urethane (Prolabo, Paris, France); Evans blue dye, formamide, histamine dihydrochloride, thiorphan (Sigma, St. Louis, MO); acetylcholine HCl (PCH, Paris, France); [Nle10]neurokinin A(4-10) (Bachem, Paris, France); SR 48968 [(S)- N-methyl-N[(4-acetylamino-4-phenylpiperidino-2-(3,4)dichlorophenyl) butyl] benzamide] (saredutant) used as hydrochloride, SR 140333 [(S)1-{2-[3-(3,4-dichlorophenyl)-1-(3-iso-propoxyphenylacetyl)piperidin-3-yl]ethyl}-4-phenyl-1-azoniabicyclo[2.2.2]octane, chloride] (chloride of nolpitantium), and SR 142801[(R)-(N)-(1-(3-(L-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl) propyl)-4-phenylpiperidin-4-yl)-N-methylacetamide] (osanetant) used as hydrochloride (Sanofi Recherche, Montpellier, France). All drugs were dissolved in saline except SR 48968, SR 140333, and SR 142801, which were dissolved in ethanol and saline. The maximum amount of ethanol injected (20 µl per 100 g body weight) did not modify the respiratory responses.

    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Effect of SR 142801 on citric acid-induced bronchoconstriction. Figure 1 shows the effects of SR 140333, SR 48968, or SR 142801 at 1 mg · kg-1 by intravenous route or their combination on the bronchoconstriction induced by aerosolized citric acid (0.4 M) in anesthetized guinea pigs. None of the compounds had an effect when given alone. When associated, SR 142801 + SR 48968 or SR 140333 + SR 48968 significantly reduced or abolished the bronchoconstriction. However, no effect was observed when SR 142801 was combined with SR 140333. 


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  		Figure 1.   Effects of pretreatments with the tachykinin receptor antagonists SR 140333, SR 48968, or SR 142801 (1 mg · kg-1, intravenously) or their association with citric acid-induced bronchoconstrictor responses in anesthetized guinea pigs. The animals were exposed to a nebulized aqueous solution of citric acid (0.4 M) for 2 min. Results are expressed as percent of the control bronchoconstriction. Values are means ± SEM (n = 6); **p < 0.01.

Effect of SR 142801 on citric acid-induced cough. SR 142801 inhibited cough induced by inhaled citric acid (0.4 M) in conscious guinea pigs by 57 ± 3% (n = 6) and 62 ± 10% (n = 7) at 0.3 and 1 mg · kg-1 by intraperitoneal route, respectively (p < 0.01) (Figure 2).


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  		Figure 2.   Effects of the tachykinin NK3 receptor antagonist SR 142801 (0.1-1 mg · kg-1, intraperitoneally) on citric acid-induced cough in unanesthetized guinea pigs. The animals were exposed to a nebulized aqueous solution of citric acid (0.4 M) for 10 min (control experiments); 48 h later, they were exposed under similar conditions to citric acid, 30 min after an administration of saline or SR 142801. Results are expressed (A) as cough number in control experiments (solid bar), after saline (open bar) or SR 142801 (hatched bar, 0.1; shaded bar, 0.3; striped bar, 1 mg · kg-1, intraperitoneally) administration or (B) as percent inhibition of the cough number versus control experiments. Values are means ± SEM; **p < 0.01. Number of animals used for each group was 6-8.

Bronchial hyperresponsiveness to acetylcholine after exposure to aerosolized citric acid. Twenty-four hours after a single exposure to aerosolized citric acid (0.4 M), airway hyperresponsiveness developed consistently in guinea pigs pretreated with thiorphan, as shown by a significant increase of acetylcholine-induced bronchoconstriction in comparison with matched saline controls (Figure 3). The maximum bronchoconstrictor responses to acetylcholine (Emax at 500 µg · kg-1) were similar in animals exposed to citric acid or saline (Table 1). The ED30 values for acetylcholine were significantly lower in animals pretreated with thiorphan and exposed to citric acid than in saline-exposed animals, showing an increase in sensitivity of approximately double. Airway hyperresponsiveness to acetylcholine following exposure to citric acid was significantly prevented by a single dose of SR 48968 or SR 142801 (1 mg · kg-1, intraperitoneally), administered 30 min before citric acid exposure (Figure 3, Table 1). At lower doses (0.1 and 0.3 mg · kg-1 intraperitoneally), SR 48968 and SR 142801 had no effects. There was no difference in baseline pulmonary inflation pressures in the different groups of animals.


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  		Figure 3.   Influence of the tachykinin receptor antagonists SR 48968 (A) and SR 142801 (B) on bronchoconstriction induced by acetylcholine (10-200 µg · kg-1, intravenously) in anesthetized guinea pig 24 h after a pretreatment with thiorphan (1 mg · kg-1, intraperitoneally) and an exposure to an aerosol of citric acid (0.4 M, 60 min). Symbols represent control responses without citric acid exposure (open box) or 24 h after citric acid exposure (solid box). Responses after tachykinin receptor antagonist pretreatment are (triangle) 0.1, (open circle) 0.3, or (solid circle) 1 mg · kg-1, intraperitoneally, given 30 min before citric acid aerosol exposure. Values are means ± SEM, n = 6-11. PIP = pulmonary inflation pressure; *p < 0.051.

                              
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TABLE 1

EFFECTS OF DIFFERENT PRETREATMENTS ON ACETYLCHOLINE-INDUCED BRONCHOCONSTRICTION

Microvascular leakage hypersensitivity to histamine after exposure to aerosolized citric acid. At 30 µg · kg-1 by intravenous route, histamine induced a more marked microvascular leakage in the trachea and main bronchi of guinea pigs exposed 24 h earlier to aerosolized citric acid (0.4 M) than in controls (Figure 4). When administered at 1 mg · kg-1 by intraperitoneal route 30 min before exposure to citric acid, both SR 140333 and SR 142801 prevented this increased histamine-induced microvascular leakage. In contrast, SR 48968 had no significant effect.


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  		Figure 4.   Potentiation by citric acid exposure 24 h earlier in animals pretreated with thiorphan (1 mg · kg-1, intraperitoneally) of Evans blue dye extravasation induced by histamine 30 µg · kg-1, intraperitoneally, in guinea pig trachea (A) or main bronchi (B) and its modifications by SR 140333, SR 4898, and SR 142801. Columns represent extravasation induced by saline (open bar) or histamine (solid bar) in control animals or by histamine after citric acid exposure in the absence (dotted bar) or after pretreatments with SR 140333 (hatched bar), SR 48968 (dashed bar) or SR 142801 (striped bar) 1 mg · kg-1, intraperitoneally, given 30 min before citric acid exposure. Values are means ± SEM, n = 6 per group; **p < 0.01.

    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Citric acid is a potent tussive agent in humans and guinea pigs (16, 17). In guinea pigs, it also provokes bronchoconstriction (11), nasal irritation (11, 14), cough (14), bronchial hyperresponsiveness to acetylcholine (18), and hypersensitivity to histamine-induced microvascular leakage (19), mimicking in that manner some of the effects of low doses of capsaicin (15, 33).

Several findings suggest that these effects are mediated by selective excitation of nonmyelinated C-fibers and by the subsequent release of sensory neuropeptides such as tachykinins (substance P, neurokinin A, neurokinin B). In guinea pigs, cough, nasal irritation, bronchoconstriction, or in vitro excitation of single airway C-fibers induced either by low doses of capsaicin or by citric acid were inhibited by the capsaicin receptor antagonist, capsazepine (10, 14, 34, 36). They were also prevented by the inorganic dye ruthenium red, which blocks the calcium channel associated with the capsaicin receptor (37, 38). On the other hand, they were suppressed by a chronic treatment with high doses of capsaicin, which provokes a complete depletion of tachykinins from sensory nerve terminals and also the degeneration of these sensory nerves (16, 18). Moreover, this has been confirmed by using tachykinin receptor antagonists; a tachykinin NK2 receptor antagonist, SR 48968, inhibited citric acid-induced bronchoconstriction (12, 13), but a tachykinin NK1 receptor antagonist, FK 888, had no effect (13). SR 48968 inhibits cough induced in conscious guinea pigs by citric acid (20, 21) and capsaicin (39), but an antitussive effect of tachykinin NK1 receptor antagonist is still debated. The tachykinin NK1 receptor antagonist CP-99,994 and SR 140333 have been reported to be inactive (10, 21), whereas FK 888 has been reported to be efficient (13). Finally, in animals previously exposed to aerosolized citric acid, SR 48968 prevented the airway hyperresponsiveness to acetylcholine (18), whereas SR 140333 inhibited the evoked potentiation of the increase in microcrovascular leakage induced by histamine (19).

Our results show that a highly potent and selective tachykinin NK3 receptor antagonist, SR 142801 (23), was able to inhibit cough, bronchial hyperresponsiveness, exaggerated plasma extravasation response to histamine, and, when combined with SR 48968, bronchoconstriction induced by inhaled citric acid. This action of SR 142801 cannot be ascribed to an antagonistic activity at tachykinin NK1 and/or NK2 receptors. Indeed, radioligand binding and well-characterized in vitro functional assays for tachykinin receptors (23, 27, 29) have clearly demonstrated that SR 142801 is a potent and selective antagonist of the tachykinin NK3 receptor. In vivo, the selectivity of SR 142801 for tachykinin NK3 receptors is clearly proved in two assays. Contrary to SR 48968, SR 142801 did not inhibit, in anesthetized guinea pigs, the bronchoconstriction induced by a selective tachykinin NK2 receptor agonist, [Nle10]neurokinin A(4-10) (23, 40, 41). Contrary to SR 140333, SR 142801 failed in guinea pigs and in dogs to inhibit the hypotension induced by a selective tachykinin NK1 receptor agonist, [Sar9,Met(O2)11] substance P (23, 42, 43).

First, our results show that SR 142801 combined with SR 48968 was able to reduce the citric acid-induced bronchoconstriction almost as completely as a combination of SR 48968 with SR 140333. However, a combination of SR 142801 with SR 140333 remained inactive. Neither SR 48968, SR 140333, nor SR 142801 were active when given alone. A cotreatment with tachykinin NK1 and NK2 receptor antagonists is often necessary in guinea pigs to induce a more complete inhibition of the effects of some bronchoconstrictive substances. Foulon and colleagues (44) have observed that bronchoconstriction induced in guinea pigs by resiniferotoxin, a vanilloid receptor agonist 100-fold more potent than capsaicin in inducing neuropeptide release from nerve ending (45), was completely blocked by a combination of SR 48968 and CP-99,994, but when given alone, neither SR 48968 nor CP-99,994 produced a significant inhibition. Bertrand and coworkers (46) have also reported that capsaicin-induced bronchoconstriction in guinea pigs was only reduced by SR 48968 but was completely abolished by the combination of SR 48968 and CP-96,345 (another tachykinin NK1 receptor antagonist). Using SR 48968 and SR 140333, similar results were obtained by Vilain and colleagues (47) when the bronchoconstriction was induced by nonirritant chemicals (dichloromethane, chloroform, or carbon dioxide). On the contrary, Satoh and colleagues (12) have shown in apparently similar experimental conditions that citric acid-induced bronchoconstriction was partially inhibited (about 65%) by SR 48968 administered alone. Nevertheless, as SR 142801 has no antagonistic activity on the tachykinin NK1 receptor (23, 27, 29, 48), our results clearly show that prevention of citric acid- induced bronchoconstriction can be only obtained by a combination of a tachykinin NK2 receptor antagonist with either a tachykinin NK1 or NK3 receptor antagonist.

Secondly, our results show that SR 142801 was able to inhibit citric acid-induced cough. Its potency was, however, lower than that of a tachykinin NK2 receptor antagonist. Indeed, in similar experimental conditions, SR 48968 has been reported to display a very potent antitussive activity with an ID50 (dose giving 50% inhibition) value of 0.03-0.05 mg · kg-1 (20). However, SR 142801 activity was obtained at doses comparable to those used to display its antagonistic effects on tachykinin NK3 receptors in various animal models (23, 28, 43).

Finally, our results show that SR 142801 was able to prevent both airway hyperresponsiveness to acetylcholine and microvascular leakage hypersensitivity to histamine in guinea pigs previously exposed to aerosolized citric acid. As SR 48968, it blocked the increased bronchial reactivity to acetylcholine (18 and this study) and, as SR 140333, it inhibited the increased histamine-induced microvascular leakage (19 and this study). Blockade of tachykinin NK3 receptors by SR 142801 can thus prevent both the tachykinin NK2 receptor-mediated airway hyperresponsiveness to acetylcholine and the tachykinin NK1 receptor-mediated microvascular leakage hypersensitivity to histamine as also observed in guinea pigs previously exposed to substance P (41).

In the present state of our knowledge, it is difficult to clarify the mechanism and/or site of action of SR 142801. First, a direct involvement of tachykinin NK3 receptors on the bronchial smooth muscle contraction has been never observed (2, 49). Secondly, a direct participation of tachykinin NK3 receptor in the impairments of vessels and endothelial cells leading to microvascular leakage can be excluded because SR 142801 failed to inhibit tachykinin- and capsaicin-induced edema in mouse ears, which is mainly mediated by tachykinin NK1 receptors and blocked by SR 140333 (52, 53). Therefore, it is likely that the effect of SR 142801 cannot be ascribed to a direct action on target organs (bronchial smooth muscle, vessels) at a postsynaptic level. Furthermore, a blockade of tachykinin NK1 and NK2 receptors by a SR 142801 metabolite can be also excluded. Indeed, 24 h after its administration at 1 mg · kg-1 intraperitoneally, SR 142801 did not inhibit [Nle10]neurokinin A(4-10)-induced bronchoconstriction in guinea pigs as well as substance P- and histamine-induced microvascular leakage in guinea pig airways (unpublished results).

As pulmonary effects of citric acid are mediated by activation of both afferent and efferent functions of sensory neurones, SR 142801 may also impair neuronal transmission. Several electrophysiological studies have reported that tachykinins elicit an important activity on the control of various neuronal and ganglionic potentials at the periphery (54, 55); among tachykinins, neurokinin B and stimulation of tachykinin NK3 receptors seem to play a predominant role. Indeed, depolarization of guinea pig bronchial parasympathetic ganglion neurons was provoked by substance P and neurokinin B (but not by neurokinin A); neurokinin B was 60-fold more potent and five times more efficient than substance P (56). Neurokinin B and [Asp5,6,methyl-Phe8] substance P (5), a selective agonist for tachykinin NK3 receptors, induced a decrease in membrane resistance (56). Interestingly, it has also been demonstrated that tachykinins mediated slow excitatory postsynaptic potential by activating tachykinin NK3 receptors in guinea pig gall bladder neurons (57). Here again, senktide (a selective agonist for tachykinin NK3 receptors) potently depolarized neurons, whereas specific tachykinin NK1 and NK2 agonists did not cause a measurable depolarization. Furthermore, senktide also had a more potent action than substance P on tonic and phasic neurones of the guinea pig celiac ganglion (58). On the basis of these data, it is not clear how such peripheral neuronal electric activities mediated by tachykinin NK3 receptors may lead to the modulation of bronchoconstriction, cough, airway hyperresponsiveness to acetylcholine, and microvascular leakage hypersensitivity to histamine without consideration of a central effect for SR 142801. If tachykinin NK3 receptor stimulation occurs at the neuronal level, other fibers than those of the parasympathetic pathway could be also implicated. Indeed, it has been demonstrated that stimulation of tachykinin NK3 receptors did not seem to facilitate cholinergic ganglionic transmission in either guinea pigs (59, 60) or rabbits (59).

In conclusion, our results show for the first time that a selective tachykinin NK3 receptor antagonist, SR 142801, can prevent cough, airway hyperresponsiveness to acetylcholine, and microvascular leakage hypersensitivity to histamine in guinea pigs previously exposed to aerosolized citric acid. They also show that it can also reduce the bronchoconstriction when the tachykinin NK2 receptor is blocked. A direct participation of tachykinin NK3 receptors in nervous control of the respiratory system is probable, especially as the SR 142801 effects seem not to be related to the blockade of tachykinin NK1 or NK2 receptors. The localization of these tachykinin NK3 receptors in the nervous system remains to be determined.

    Footnotes

Correspondence and requests for reprints should be addressed to Charles Advenier, Laboratoire de Pharmacologie, Faculté de Médecine Paris-Ouest, 15, Rue de l'Ecole de Médecine, 75006 Paris, France.

(Received in original form May 20, 1997 and in revised form January 6, 1998).

Presented in part at the annual Meeting of the American Thoracic Society, San Francisco, California, May 1997.
    References
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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