Role of tachykinins in bronchoconstriction induced by intravenous administration of bradykinin in guinea-pigs (original) (raw)
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In vitro-induced human airway hyperresponsiveness to bradykinin
European Respiratory Journal, 1998
Airway inflammation is one of the main features of asthma. It has been well established that people with respiratory infections may experience increased bronchial reactivity and impaired bronchial airflow . Inhalation of endotoxin or lipopolysaccharide (LPS), a component of the outer cell wall of Gram-negative bacteria, has been reported to induce airway hyperresponsiveness in both normal [3] and asthmatic subjects . The pathophysiological mechanisms underlying these changes after administration of LPS to the airways are not fully understood. Effects of LPS are likely to be indirect, through the activation of various inflammatory cells which release the different endogenous inflammatory mediators and cytokines responsible for the host response. Among them, interleukin (IL)-1β is notable [6-8] and has been described as inducing airway hyperresponsiveness. Indeed, intratracheal administration of IL-1β has been shown to induce airway hyperresponsiveness to bradykinin in rats .
The effect of peptidase inhibitors on bradykinin-induced bronchoconstriction in guinea-pigs in vivo
British Journal of Pharmacology, 1990
1 Bradykinin (BK) instilled directly into the airway lumen caused bronchoconstriction in anaesthetized, mechanically ventilated guinea-pigs in the presence of propranolol (1 mg kgi.v.) The geometric mean dose of BK required to produce 100% increase in airway opening pressure (PD100) was 22.9 nmol (95% c.i. 11.7-44.6 nmol). 2 The dose-response curve for the effect of instilled BK was significantly shifted to the left by the angiotensin converting enzyme (ACE) inhibitor, captopril (5 and 50nmol instillation, PD100 = 3.0, 95% c.i. 0.98-8.9, and 2.0 nmol, 95% ci. 0.65-6.2 nmol, respectively). 3 The neutral endopeptidase (NEP) inhibitor, phosphoramidon (5 and 50nmol instillation) also shifted the dose-response curve for the effect of instilled BK; the PD100 values = 2.2 (95% c.i. 0.40-11.7) and 1.8 nmol (95% c.i. 0.87-3.5 nmol), respectively. 4 After pretreatment with captopril (50nmol) and phosphoramidon (50nmol) in combination, the doseresponse curve for the effect of instilled BK (PD100 = 1.1 nmol, 95% c.i. 0.37-3.2 nmol) was similar to that obtained in the presence of each inhibitor used alone. 5 The kininase I inhibitor, DL-2-mercaptomethyl-3-guanidinoethylthiopropionic acid (50 nmol instillation) failed to alter the dose-response curve to instilled BK (PD1oo = 14.6nmol, 95% c.i. 6.7-32.0 nmol). 6 These data suggest that both ACE and NEP degrade BK in the airway lumen, but that kininase I is not involved.
European Journal of Pharmacology, 1992
We studied the effects of indomethacin (10 mg/kg i.v.), a cyclooxygenase inhibitor, and OKY-046 (1, 10 and 30 mg/kg i.v.), a selective thromboxane synthetase inhibitor, on airflow obstruction and airway plasma exudation induced by bradykinin (150 nmol) instilled by the airway route to anesthetized guinea pigs. To do this, we studied changes in lung resistance (R L) and extravasation of Evans Blue dye respectively. Instilled bradykinin produced an immediate and marked increase in R L which peaked at approximately 30 s. We also observed a delayed increase in R L, reaching a second peak at approximately 3 min. Bradykinin produced airway plasma exudation at all airway levels, measured as extravasation of Evans Blue dye. Indomethacin significantly inhibited both the immediate and the delayed increase in RL after bradykinin. OKY-046 had a similar significant and dose-dependent inhibitory effect on these responses. In addition, both drugs inhibited bradykinin-induced Evans blue dye extravasation in intrapulmonary airways. Bradykinin instilled by the airway route significantly decreased systemic blood pressure but this effect was not altered in animals pretreated with either indomethacin or OKY-046. We conclude that the bronchoconstrictor response and airway plasma exudation induced by instilled-bradykinin may be mediated in part via thromboxane A~ generation.
The Lancet, 1992
page 1109). 15. Trigg PI. Qinghaosu (artemisinin) as an antimalarial drug. Econ Med Plant Res 1987; 3: 20-54. 16. Wang Tongyin, Xu Ruchang. Clinical studies of treatment of falciparun malaria with artemether, a derivative of qinghaosu. J Tradit Clin Med 1985; 5: 240-42. 17. Harinasuta T, Bunnag D, Lasserre R, Leimer R, Vanijanont S. Trials of mefloquine in vivax and of mefloquine plus 'Fansidar' in falciparum malaria. Lancet 1985; i: 885-88. 18. Bunnag D, Viravan C, Looareesuwan S, Karbwang J, Harinasuta T Clinical trial of artesunate and artemether on multidrug resistant falciparum malaria in Thailand; a preliminary report. Southeast Asian J Trop Med Public Health 1991; 22: 380-85. 19. Harinasuta T, Bunnag D, Wernsdorfer WH. A phase II clinical trial of mefloquine in patients with chloroquine-resistant falciparum malaria in Thailand. Bull World Health Organ 1983; 61: 299-305.
Journal of Pharmacology …, 2010
Inhaled bradykinin causes bronchoconstriction in asthmatic subjects but not nonasthmatics. To date, animal studies with inhaled bradykinin have been performed only in anesthetized guinea pigs and rats, where it causes bronchoconstriction through sensory nerve pathways. In the present study, airway function was recorded in conscious guinea pigs by whole-body plethysmography. Inhaled bradykinin (1 mM, 20 s) caused bronchoconstriction and influx of inflammatory cells to the lungs, but only when the enzymatic breakdown of bradykinin by angiotensin-converting enzyme and neutral endopeptidase was inhibited by captopril (1 mg/kg i.p.) and phosphoramidon (10 mM, 20-min inhalation), respectively. The bronchoconstriction and cell influx were antagonized by the B 2 kinin receptor antagonist 4-(S)-amino-5-(4-{4-[2, 4-dichloro-3-(2,4-dimethyl-8-quinolyloxymethyl)phenylsulfonamido]-tetrahydro-2H-4-pyranylcarbonyl}piperazino)-5oxopentyl](trimethyl)ammonium chloride hydrochloride (MEN16132) when given by inhalation (1 and 10 M, 20 min) and are therefore mediated via B 2 kinin receptors. However, neither intraperitioneal MEN16132 nor the peptide B 2 antagonist icatibant, by inhalation, antagonized these bradykinin responses. Sensitization of guinea pigs with ovalbumin was not sufficient to induce airway hyperreactivity (AHR) to the bronchoconstriction by inhaled bradykinin. However, ovalbumin challenge of sensitized guinea pigs caused AHR to bradykinin and histamine. Infection of guinea pigs by nasal instillation of parainfluenza-3 virus produced AHR to inhaled histamine and lung influx of inflammatory cells. These responses were attenuated by the bradykinin B 2 receptor antagonist MEN16132 and H-(4-chloro)DPhe-2Ј(1-naphthylalanine)-(3-aminopropyl)guanidine (VA999024), an inhibitor of tissue kallikrein, the enzyme responsible for lung synthesis of bradykinin. These results suggest that bradykinin is involved in virus-induced inflammatory cell influx and AHR. This work was supported by Vantia Ltd (Southampton, UK). Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
British Journal of Pharmacology, 1993
The mechanisms behind bradykinin-induced effects in the airways are considered to be largely indirect. The role of cholinergic nerves and eicosanoids, and their relationship in these mechanisms were investigated in guinea-pigs. 2 The role of cholinergic nerves was studied in animals given atropine (1 mg kg-', i.v.), hexamethonium (2 mg kg-', i.v.), or vagotomized. To study the role of eicosanoids, animals were pretreated with a thromboxane A2 (TxA2) receptor antagonist (ICI 192,605; 106 mol kg-', i.v.) or with a leukotriene (LT) receptor C4/D4/E4 antagonist (ICI 198,615; 106 mol kg-', i.v.). 3 After pretreatment with a drug, bradykinin (150 nmol) was instilled into the tracheal lumen. We measured both airway insufflation pressure (Pi), to assess airway narrowing, and the content of Evans blue dye in airway tissue, to assess plasma exudation. 4 Bradykinin instillation into the trachea caused an increase in Pi and extravasation of Evans blue dye. The increase in Pi was significantly attenuated by atropine or the TxA2 receptor antagonist, but not by hexamethonium, vagotomy or the LT receptor antagonist. 5 The bradykinin-induced exudation of Evans blue dye was significantly attenuated in the intrapulmonary airways by the TxA2 receptor antagonist, but not by atropine, hexamethonium, cervical vagotomy or the LT receptor antagonist. 6 A thromboxane-mimetic, U-46619 (20 nmol kg-', i.v. or 10 nmol intratracheally), caused both an increase in Pi and extravasation of Evans blue dye at all airway levels. Atropine pretreatment slightly attenuated the peak Pi after the intratracheal administration of U-46619, but not after i.v. administration. 7 We conclude that peripheral cholinergic nerves are involved in bradykinin-induced airflow obstruction but not plasma exudation, and that TxA2 is involved in both airflow obstruction and airway plasma exudation induced by bradykinin given via the airway route. TxA2-induced airflow obstruction is mediated only to a minor degree, via the release of acetylcholine in the airways.
Journal of Pharmacology and Experimental Therapeutics, 2010
Inhaled bradykinin causes bronchoconstriction in asthmatic subjects but not nonasthmatics. To date, animal studies with inhaled bradykinin have been performed only in anesthetized guinea pigs and rats, where it causes bronchoconstriction through sensory nerve pathways. In the present study, airway function was recorded in conscious guinea pigs by whole-body plethysmography. Inhaled bradykinin (1 mM, 20 s) caused bronchoconstriction and influx of inflammatory cells to the lungs, but only when the enzymatic breakdown of bradykinin by angiotensin-converting enzyme and neutral endopeptidase was inhibited by captopril (1 mg/kg i.p.) and phosphoramidon (10 mM, 20-min inhalation), respectively. The bronchoconstriction and cell influx were antagonized by the B 2 kinin receptor antagonist 4-(S)-amino-5-(4-{4-[2, 4-dichloro-3-(2,4-dimethyl-8-quinolyloxymethyl)phenylsulfonamido]-tetrahydro-2H-4-pyranylcarbonyl}piperazino)-5oxopentyl](trimethyl)ammonium chloride hydrochloride (MEN16132) when given by inhalation (1 and 10 M, 20 min) and are therefore mediated via B 2 kinin receptors. However, neither intraperitioneal MEN16132 nor the peptide B 2 antagonist icatibant, by inhalation, antagonized these bradykinin responses. Sensitization of guinea pigs with ovalbumin was not sufficient to induce airway hyperreactivity (AHR) to the bronchoconstriction by inhaled bradykinin. However, ovalbumin challenge of sensitized guinea pigs caused AHR to bradykinin and histamine. Infection of guinea pigs by nasal instillation of parainfluenza-3 virus produced AHR to inhaled histamine and lung influx of inflammatory cells. These responses were attenuated by the bradykinin B 2 receptor antagonist MEN16132 and H-(4-chloro)DPhe-2Ј(1-naphthylalanine)-(3-aminopropyl)guanidine (VA999024), an inhibitor of tissue kallikrein, the enzyme responsible for lung synthesis of bradykinin. These results suggest that bradykinin is involved in virus-induced inflammatory cell influx and AHR. This work was supported by Vantia Ltd (Southampton, UK). Article, publication date, and citation information can be found at
Cross refractoriness between bradykinin and hypertonic saline challenges in asthma
Journal of Allergy and Clinical Immunology, 1995
Background: Repeated inhalation of bradykinin and hypertonic saline leads to refractoriness of the bronchoconstrictor response in asthma. It is not known whether cross-refractoriness exists between these stimuli. Objective: We postulated that repeated bradykinin and hypertonic saline bronchial challenges might reduce the airway response to subsequent hypertonic saline and bradykinin challenges, respectively. Methods: Eleven atopic asthmatic subjects underwent two concentration-response studies, separated by 1 hour, with either inhaled histamine or bradykinin. After recovery, a hypertonic saline challenge was performed. During the next phase, nine subjects underwent two concentration-response studies, separated by I hour, with hypertonic saline. After recovery, a bradykinin challenge was performed. Results: On the histamine study day, the mean provocative volume of agonist required to produce 20% drop in forced expiratory volume in 1 second (PD:o) hypertonic saline was 220. 7 L (+_42. 7 L) and this was not significantly different from that measured at baseline. On the bradykinin study day, the geometric mean provocative concentration of agonist required to produce a 20% drop in forced expiratory volume in 1 second (PCeo) was 0.39 mg/ml (0.01 to 11. 73 mg/ml) fo r the first test and significantly higher at 1.38 mg/m ! (0.01 to >16.0 mg/ml) for the second test (p = 0.006). The hypertonic saline PD2o increased significantly from a baseline of 159.2 L (+_27.3 L) to 377.6 (+_64.7L) (p = 0.003). On the hypertonic saline study day, the mean PD2o was 152.8 L for the first test, and 337. 7 L for the second test (p = 0.01). PC2o bradykinin increased significantly from a baseline of 0.57 to 2.56 mg/ml (p = 0.02). A significant correlation was found between loss of response to bradykinin and to hyperton& saline (rs, O. 63 and O. 76). Conclusion: Refractoriness produced by repeated exposure of the airways to bradykinin and hypertonic saline results in loss of responsiveness to hypertonic saline and bradykinin respectively, suggesting a shared mechanism for refractoriness produced by these stimuli. (J ALLERGY CLIN 1MMUNOL 1995,'96:502-9.) Bradykinin is a potent vasoactive nonapeptide formed as cleavage product from the action of plasma kallikrein on high molecular weight kininogen. When inhaled by asthmatic subjects, bradykinin causes bronchoconstriction. 1-3 Bradykinin pro-From the 502 Abbreviations used FEVI: Forced expiratory volume in 1 second HS: Hypertonic saline PC2o: Provocative concentration of agonist required tO produce 20% drop in FEV~ PD2o: Provocative volume of agonist required to produce 20% drop in FEV 1 duces many of its effects by interacting with specific receptors, designated [32. Although in vivo structure-activity studies have suggeste d that bradykinin produces bronchoconstriction by stimulating [32 receptors, 2 the physiologic mechanism(s) involved are not clearly understood. Although both the J ALLERGY CLIN IMMUNOL Rajakulasingam et ai. 503 VOLUME 96, NUMBER 4
Effect of inhaled bradykinin on indices of airway responsiveness in asthmatic subjects
European Respiratory Journal, 1994
in nd di ic ce es s o of f a ai ir rw wa ay y r re es sp po on ns si iv ve en ne es ss s i in n a as st th hm ma at ti ic c s su ub bj je ec ct ts s ABSTRACT: Asthma is characterized by airway hyperresponsiveness, a physiopathological abnormality which may result from the complex interplay between inflammatory cells and proinflammatory mediators. Although kinins are thought to play a role in the pathogenesis of bronchial asthma, it is not known whether bradykinin is able to induce airway hyperresponsiveness.