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Formoterol and Salbutamolinhibit Bradykinin- and Histamine-Induced

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Formoterol and Salbutamolinhibit Bradykinin- and Histamine-Induced Br. J. Pharmacol. (1992), 105, 792-798 (D Macmillan Press Ltd, 1992 Formoterol and salbutamol inhibit bradykinin- and histamine-induced airway microvascular leakage in guinea-pig 1C. Advenier, Y. Qian, J-D. Law Koune, M. Molimard, *M-L. Candenas & E. Naline Laboratoire de Pharmacologie, Faculte de Medecine Paris-Ouest, 15, rue de l'Ecole de Medecine, F-75270 Paris Cedex 06, France and *Centro de Productos naturales Organicos "Antonio Gonzalez", Instituto Universitario de Bio-Organica, Universidad de La Laguna, Carretera de la Esperanza, 2, 38206 La Laguna, Tenerife, Spain 1 The effects of the #2-adrenoceptor agonists, salbutamol and formoterol, on the increase of micro- vascular permeability induced by histamine or bradykinin in guinea-pig airways have been studied in vivo. Extravasation of intravenously injected Evans blue dye was used as an index of permeability. The effects of salbutamol and formoterol on the increase in pulmonary airway resistance induced by histamine or bradykinin have also been studied. 2 The increase in pulmonary airway resistance induced by histamine or bradykinin was totally inhibited by salbutamol and formoterol. The ED50 of the two mediators were 0.59 + 0.21 (n = 5) and 0.20 + 0.14 (n = 5) pg kg'- respectively for salbutamol, and 0.13 + 0.12 (n = 6) and 0.02 + 0.01 (n = 6) pg kg- respectively for formoterol. 3 Salbutamol (10 and 30pgkg-1) and formoterol (1 and lOpgkg-1) inhibited the increase of micro- vascular permeability induced by histamine (30pgkg-') in the guinea-pig airways. The inhibitory effect was predominant in the trachea and the main bronchi, with a maximum inhibition of 20 to 50%. The two drugs had little or no inhibitory effect on the other structures studied, viz. nasal mucosa, larynx, proximal and distal intrapulmonary airways. 4 Salbutamol and formoterol (1 and 10pgkg-1) abolished the increase in microvascular permeability induced by bradykinin (0.3 Mg kg'- ). This inhibitory effect of two f-adrenoceptor stimulants was predomi- nant in the trachea and the nasal mucosa where it was observed with 1 pg kg-1 of the f-adrenoceptor agonists. In the main bronchi, and in the proximal and distal intrapulmonary airways, the effects of - bradykinin were abolished by 10 pg kg of formoterol and salbutamol. 5 The effects of bradykinin, but not those of histamine, were significantly reduced (nasal mucosa, main bronchi and distal intrapulmonary airways) or abolished (trachea, proximal intrapulmonary airways) by morphine 10mgkg-1, i.v. These results suggest that an indirect effect, through non-adrenergic non- cholinergic (NANC) nerves is involved in the action of bradykinin on the microvascular permeability. 6 In conclusion, intravenously injected f-adrenoceptor stimulants can inhibit, partially or totally, the increase of airways microvascular permeability induced by intravenous histamine or bradykinin. However, these effects require doses that are higher than those that inhibit the increase in pulmonary airway resistance induced by these mediators. As suggested by the results obtained with morphine, the higher efficacy of fi2-adrenoceptor agonists versus bradykinin may occur through activation of presynap- tic receptors of the non-adrenergic non-cholinergic (NANC) nerves preventing release of inflammatory neuropeptides such as substance P and neurokinin A. Keywords: Histamine; bradykinin; salbutamol; formoterol; vascular permeability; plasma exudation; plasma leakage; airway oedema; asthma Introduction airways, bradykinin is the mediator that is most consistently increased in nasal lavages from patients with nasal symptoms Bradykinin (BK) is a naturally occurring inflammatory non- associated with rhinovirus colds (Naclerio et al., 1987). In apeptide which is generated either by cleavage of a low molec- addition bradykinin and histamine levels are increased in ular weight kininogen by tissue kallikrein or by activation of nasal secretions from individuals with allergic rhinitis (Proud the plasma proteolytic cascade (Regoli & Barabe, 1980); it et al., 1983). may be an important mediator of inflammatory airway dis- Conflicting results have been reported concerning the effects eases such as asthma (Fuller et al., 1987; Barnes et al., 1988) of f-adrenoceptor stimulants on the increase of microvascular or allergic rhinitis (Proud et al., 1983; 1988). Asthmatic permeability induced in the airways by various mediators. patients have elevated kinin concentrations in plasma (Abe et Erjefalt & Persson (1986) have shown that terbutaline attenu- al., 1967) and in nasal and bronchoalveolar lavage fluid after ates histamine- and leukotriene D4 (LTD4)-induced micro- antigen challenge (Baumgarten et al., 1985; Christiansen et al., vascular leakage in cat and guinea-pig trachea, whereas 1987). Both intravenous and inhaled bradykinin cause bron- Boschetto et al. (1989) have found that salbutamol has no choconstriction in asthmatic, but not in normal subjects effect on the action of the platelet activating factor (PAF). (Simonsson et al., 1973; Newball et al., 1975; Fuller et al., More recently, Norris et al. (1990) have reported that salbuta- 1987; Polosa et al., 1990). Bradykinin causes not only bron- mol inhibits neurogenic inflammation in the rat trachea, while choconstriction but also stimulation of sensory nerves Tokuyama et al. (1991) have demonstrated that inhaled for- (Kaufman et al., 1980; Dixon & Barnes, 1989), increase of moterol and salbutamol reduce the histamine-induced airway mucus secretion (Davies et al., 1982) and airway micro- microvascular leakage in guinea-pigs. vascular leakage with oedema formation (Saria et al., 1983; The purpose of this study was to evaluate and compare the Rogers et al., 1990), which may be relevant to asthma effects on airway microvasculature of two f-adrenoceptor (Persson, 1987; Chung et al., 1990). Concerning the upper stimulants, salbutamol and formoterol, against the effects of intravenous bradykinin and histamine. Formoterol is a new 1 Author for correspondence. f32-adrenoceptor agonist which has been shown to be more BRADYKININ-INDUCED AIRWAY MICROVASCULAR LEAKAGE 793 potent than salbutamol and, when given by inhalation, acts After a further 1 min, saline (1 ml kg- 1), bradykinin for 12h compared with 4h for salbutamol (Lofdahl & (0.3pgkg-1) or histamine (30pgkg-1) were injected; Smin Svedmyr, 1989; Becker & Simons, 1989; Wallin et al., 1990; later, the thorax was opened and a blunt-ended, 13-gauge Malo et al., 1990). We have also compared the effects exerted needle passed into the aorta. The ventricles were cross- by salbutamol and formoterol on increased microvascular clamped and blood was expelled through an incision in the permeability with their effects on increase of airway resistance right atrium at 80mmHg pressure with about 100ml saline induced by histamine and bradykinin. (pH 5.5), in order to remove the intravascular dye from the systemic and pulmonary circulations (Evans et al., 1988; Jin et al., 1988; Ichinose & Barnes, 1990b) until the perfusate was Methods clear. The lungs were then removed. The connective tissues, vasculature, and parenchyma were gently scraped, and the Measurement ofairway resistance airways were divided into four components: lower part of trachea, main bronchi, and proximal (the proximal 3 mm Tricoloured guinea-pigs weighing from 0.4 to 0.6 kg were portion) and distal intrapulmonary airways (Udaka et al., anaesthetized with urethane (1.25gkg-1, i.p.). A cannula was 1970; Rogers et al., 1989). Samples of mucosa and of larynx inserted into the trachea and the animals were allowed to were also removed and prepared under similar conditions. breath spontaneously. Pulmonary airway resistance (RAW) was The tissues were blotted dry, placed in preweighed tubes, and determined according to the methods of Amdur & Mead reweighed, and their dye content was extracted in formamide (1958) and Advenier et al. (1972). Transpulmonary pressure at 37°C for 18 h. Dye concentration was quantified by light was measured by needle pleural puncture, and airflow and absorbance at 620 nm (DCP spectrophotometer, Vital, 6907 tidal volume by plethysmography. All values were contin- AC Dieren, Holland) and its tissue content (ng dye mg-' wet uously recorded on a 7700 Hewlett Packard recorder. wt tissue) was calculated from a standard curve of dye concen- The action of formoterol or salbutamol on the broncho- trations in the 0.5 to 10 pg ml -1 range. constriction induced by histamine or bradykinin was tested on The doses of histamine (30 pg kg- ) and bradykinin groups of 4 to 6 guinea-pigs, one group for each broncho- (0.3pgkg-1) were chosen from preliminary experiments and constrictor and each substance. Each animal received 2-3 i.v. gave 30 to 70% of maximal effect (Table 1). In experiments doses of histamine (30pgkg-1) or bradykinin (0.3.pgkg-1) at with bradykinin, all animals were pretreated with captopril intervals of 15min and the mean response was calculated. (5 mg kg -) 15 min before the beginning of experimentation to Formoterol (0.03 to lpgkg-') or salbutamol (0.1 to block bradykinin metabolism (Ichinose & Barnes, 1990a) and 3 pgkg-1) were then administered i.v., and one of the medi- potentiate its effects (Table 1). Time to remove tissues was ators was injected once more 5 min after each dose. The chosen in agreement with Boschetto et al. (1989) who have results are expressed as percentage changes of the initial shown that the maximal (but non significant) effect of f2 effects. agonist (salbutamol) against PAF (platelet-activating factor) Basal values of pulmonary resistance were 0.47 was observed 5 min after administration and with Rogers et al. + 0.07 cmH2Oml 1 s_ 1 (n = 22). Histamine (30 pg kg- 1) and (1990) who have shown that bradykinin-induced leakage was bradykinin (0.3upgkg-1) doses were chosen to raise airway maximal in all airways after 5 min. resistance by 80 to 200%. In experiments with bradykinin, all animals were pretreated with captopril (5mg kg 1) 15min before the beginning of the Drugs metabolism & experiment to block bradykinin (Ichinose The drugs used were: bradykinin (gift of Professor Regoli, Barnes, 1990a) and potentiate its effects.
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