Bronchoconstriction induced by citric acid inhalation in guinea pigs: role of tachykinins, bradykinin, and nitric oxide (original) (raw)
Related papers
Bronchoconstriction Induced by Citric Acid Inhalation in Guinea Pigs
American Journal of Respiratory and Critical Care Medicine
Gastroesophageal acid reflux into the airways can trigger asthma attacks. Indeed, citric acid inhalation causes bronchoconstriction in guinea pigs, but the mechanism of this effect has not been fully clarified. We investigated the role of tachykinins, bradykinin, and nitric oxide (NO) on the citric acidinduced bronchoconstriction in anesthetized and artificially ventilated guinea pigs. Citric acid inhalation (2-20 breaths) caused a dose-dependent increase in total pulmonary resistance (R L ). R L value obtained after 10 breaths of citric acid inhalation was not significantly different from the value obtained after 20 breaths (p ϭ 0.22). The effect produced by a half-submaximum dose of citric acid (5 breaths) was halved by the bradykinin B 2 receptor antagonist HOE 140 (0.1 mol и kg Ϫ 1 , intravenous) and abolished by the tachykinin NK 2 receptor antagonist SR 48968 (0.3 mol и kg Ϫ 1 , intravenous). Bronchoconstriction induced by a submaximum dose of citric acid (10 breaths) was partially reduced by the administration of HOE 140, SR 48968, or the NK 1 receptor antagonist CP-99,994 (8 mol и kg Ϫ 1 ,
American Journal of Respiratory and Critical Care Medicine, 1998
Aerosolized citric acid induces several pulmonary effects including bronchoconstriction, airway inflammation, and cough. Evidence from the use of tachykinin NK 1 and NK 2 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 NK 3 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 и kg Ϫ 1 by intraperitoneal route, significantly inhibited cough in conscious guinea pigs by 57 Ϯ 3 and 62 Ϯ 10% (n ϭ 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 NK 2 receptor antagonist, SR 48968 (saredutant). In guinea pigs pretreated with thiorphan (1 mg и kg Ϫ 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 и kg Ϫ 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 NK 3 receptors are involved in citric acid-induced effects on airways. Daoui S, Cognon C, Naline E, Emonds-Alt X, Advenier C. Involvement of tachykinin NK 3 receptors in citric acid-induced cough and bronchial responses in guinea pigs.
European Respiratory Journal, 1996
To elucidate the role of tachykinins in bronchoconstriction induced by intravenous administration of bradykinin (Bk), we studied the effects of FK224, a neurokinin-1 (NK 1) and neurokinin-2 (NK 2) receptor antagonist, on the bronchoconstriction induced by intravenous (i.v.) administration of Bk (5-100 µg•kg-1) in guinea-pigs. Total pulmonary resistance (RL) was measured using a pressure-volume sensitive body plethysmograph in anaesthetized artificially ventilated guinea-pigs pretreated with atropine (1 mg•kg-1) and propranolol (1 mg•kg-1). In the control group, i.v. administration of Bk produced a dose-dependent increase in RL. In animals pretreated with FK224, bronchoconstriction induced by higher doses of Bk (10, 50 and 100 µg•kg-1) was significantly reduced, whilst the bronchoconstriction caused by lower doses of Bk (5 and 7.5 µg•kg-1) was not. Pretreatment with a combination of FK224 and indomethacin markedly inhibited the bronchoconstriction induced by each dose of Bk compared with the groups pretreated with FK224 alone. Although pretreatment with indomethacin alone significantly reduced RL at a high dose of Bk (50 µg•kg-1), the reduction was significantly lower than that produced by a combination of FK224 and indomethacin. These results suggest that intravenous administration of a high dose of bradykinin causes bronchoconstriction both by cyclo-oxygenase products and by release of tachykinins.
Role of substance P and tachykinin receptor antagonists in citric acid-induced cough in pigs
European Journal of Pharmacology, 2000
. The purpose of this work was to investigate the role of tachykinins in cough induced by citric acid 0.8 M in pigs. With this object, we have studied the effect of citric acid on substance P content in the tracheo-bronchial tree and the effects of substance P and of tachykinin receptor antagonists on citric acid-induced cough. Citric acid exposure significantly increased substance P concentration in both broncho-alveolar and tracheal lavage fluids, while it decreased significantly the substance P content in tracheal mucosa. Substance P did not elicit cough, but significantly potentiated the citric acid-induced cough frequency. Tachykinin NK , NK or NK receptor 1 2 3 Ž . Ž . Ž . antagonists, SR 140333 nolpitantium , SR 48968 saredutant and SR 142801 osanetant , respectively, significantly inhibited citric acid-induced cough. The same inhibitory effect of tachykinin receptor antagonists was observed, when substance P was nebulised before citric acid challenge. We conclude that citric acid induces in pigs a release of substance P in the tracheo-bronchial tree, which plays a sensitising role on the cough reflex. The involvement of tachykinin NK , NK , NK receptors are also demonstrated in this reflex. 1 2 3 q
Tachykinin receptor antagonists inhibit hyperpnea-induced bronchoconstriction in guinea pigs
Journal of Clinical Investigation, 1993
We tested the hypothesis that hyperpnea-induced bronchoconstriction (HIB) and hyperpnea-induced bronchovascular hyperpermeability (HIBVH) are mediated through stimulation of NK-1 and NK-2 receptors in guinea pigs. We first established the efficacy and selectivity of (±) CP-96,345 (3 mg/kg i.v.) and of 968 (300 ,ug/kg i.v.) as NK-1 and NK-2 antagonists, respectively. (±) CP-96,345 substantially attenuated bronchoconstriction and systemic vascular leak caused by administration of Sar9, Met(02)"-Substance P (a specific NK-1 agonist), but had no effect upon bronchoconstriction induced by selective NK-2 stimulation with Nle -Neurokinin A14-10I. Conversely, SR-48,968 antagonized the bronchoconstrictor response to Nle'0-NKA14-101, right-shifting the doseresponse curve by 2 log units, but had no effect on Sar9, Met(02)"-SP-induced bronchoconstriction. Anesthetized, tracheostomized, opened-chest male Hartley guinea pigs were pretreated with (±) CP-96,345 (3 mg/kg i.v.), SR48,968 (300 ,ug/kg i.v.), or their respective vehicles, and Evans blue dye (30 mg/kg i.v.) to label circulating albumin. 10 min isocapnic dry gas hyperpnea (12 ml/kg, 150 breaths/min) provoked HIB and HIBVH in vehicle-treated animals. (±) CP-96,345 reduced the magnitude of HIB by one-half (peak posthyperpnea RL 7.8±1.9 ISEI times prehyperpnea baseline versus 16.1±2.6, vehicle-treated; P < 0.0001, ANOVA); SR48,968 blocked HIB more completely (peak posthyperpnea RL 5.1±1.7 ISEI times prehyperpnea baseline versus 19.3±2.8, vehicle-treated; P < 0.0001, ANOVA). Neither drug reduced HIBVH. We conclude that dry gas hyperpnea causes bronchoconstriction in guinea pigs through activation of tachykinin receptors. The differential effects of neurokinin receptor blockade on HIB and HIBVH demonstrate that hyperpnea-induced airflow obstruction is not primarily a consequence of hyperpnea-induced bronchovascular leak. (J. Clin. Invest. 1993. 92:315-323.) Key words: exercise-induced asthma-tachykinin * respiratory heat and water loss * bronchovascular hypermeability * C-fiber
European Journal of Pharmacology, 1992
Bronchospasm induced by i.v. injection of equieffective doses of acetylcholine, capsaicin or selective tachykinin receptor agonists ([Sar9]Sp sulfone or [/3-AlaS]neurokinin A (NKA-4-10)) (for NK 1 and NK 2 receptors, respectively) was studied in anaesthetized guinea-pigs. The NK 1 and NK 2 receptor antagonists, (+)-CP96,345 (3/zmol/kg i.v.) and MEN 10,376 (3/~mol/kg i.v.), selectively abolished the bronchoconstriction induced by the respective agonist, showing that both NK 1 and NK 2 receptors mediate bronchoconstriction in guinea-pig airways and that they are activated independently. Capsaicin-induced bronchospasm was inhibited by atropine (1.5/zmol/kg i.v.) and MEN 10,376 (3/zmol/kg i.v.), but unaffected by (+)-CP96,345 (3/zmol/kg i.v.). Hexamethonium (79 /zmol/kg i.v.), propranolol (17 ~mol/kg i.v.) and physostigmine (0.9 /xmol/kg i.v.) enhanced the airway constriction induced by acetylcholine, capsaicin, [Sar9]Sp sulfone or [fl-AlaS]NKA-(4-10) while guanethidine (67/xmol/kg s.c. for two days) increased only bronchoconstriction induced by capsaicin or the selective NK 2 receptor agonist. In hexamethonium-treated animals, MEN 10,376 still abolished the increase in insuffiation pressure induced by [fl-AlaS]NKA-(4-10) and reduced the increase elicited by capsaicin. In summary, in anaesthetized guinea pig i.v. capsaicin-induced bronchospasm through activation of postjunctional NK 2 (but not NK 1) receptors along with activation of cholinergic pathways. This motor response is moderated by the simultaneous stimulation of a sympathetic bronchodilating mechanism(s), possibly through activation of NK 2 receptors localized in sympathetic ganglia.
Tachykinin receptors in the guinea-pig isolated bronchi
European Journal of Pharmacology, 1991
The aim of the study was to assess which tachykinin receptors mediate the contractile response in the gtiea-pig isolated bronchi. Experiments with natural tachykinins and receptor-selective tachykinin agonists were performed in the absence or presence of peptidase inhibitors and in bronchi pretreated with phenoxybenzamk Both NK-1 (substance P, substaoce P methylester and septide) and NK-2 (neurokinin A, [/3-Alas]neurokinin A-(4-10) and MDL 28,564) receptor agonists prodLmd concentration-dependent contraction. NK-3 agonists (set&tide and [hfePhe']neurokinin B) were active only at high concentrations. Ph~noxybe~ e pre~atm~t reduced the maximal response to N&l agonists and produced a ~~~~d shift of the curve to WC-2 agonists, without depression of the maximum. Five tachykinin antagonists selective for the N&l (L 668,169) o: the NK-2 (MEN 10,207, MEN 10,376, L 659,877 and R 396) receptor were tested against substance P methylester and [&4ia8]neurokinin A-(4-10). The results indicated that these receptor-selective antagonists maintain their characteristic even when tested in a multireceptor assay such as the guinea-pig bronchus. The rank order of potency of NK-2 antagonists against [/3-Ala8]neurokinin A-(4-10) was MEN 10,207 = MEN 10,376) L 659,877 = R 396. This pattern, with the observation of the full agonist activity of MDL 28,564, indicates that in addition to NK-1 receptors, NK-2 receptors also are present in the +inea-pig bronchi and belong to the same subtype INK-2A) as present in the rabbit pulmonary artery.
2003
Gastroesophageal acid reflux (GER) is a common disorder associated with the exacerbation of asthma. In this study we investigated the effects on the airways of intraoesophageal HCl instillation in the rabbit and the role of tachykinins in these effects. In anaesthetized New Zealand rabbits bronchopulmonary functions [total lung resistance (R L) and dynamic compliance (C dyn)] were calculated before and after HCl intraoesophageal instillation. Infusion of HCl induced a significant bronchoconstriction (P < 0.05) in the terms of R L and C dyn changes, that were increased by phosphoramidon pre-treatment and reduced by capsaicin pre-treatment. Moreover, a pretreatment with SR 48968, a tachykinin NK 2 receptor antagonist, or SR 140333, a NK 1 receptor antagonist, significantly inhibited the bronchoconstriction induced by intraoesophageal HCl infusion in terms of R L and C dyn changes. Finally, the HCl induced bronchoconstriction was unaffected by SR 142801, a tachykinin NK 3 receptor antagonist. In conclusion these results suggest that bronchoconstriction induced by intraoesophageal HCl infusion is mainly dependent on the release of tachykinins and that both NK 1 and NK 2 tachykinin receptors are involved.