Formoterol and salbutamol inhibit bradykinin‐ and histamine‐induced airway microvascular leakage in guinea‐pig

Abstract

1 The effects of the #2-adrenoceptor agonists, salbutamol and formoterol, on the increase of microvascular 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 kgrespectively for formoterol.3 Salbutamol (10 and 30pgkg-1) and formoterol (1 and lOpgkg-1) inhibited the increase of microvascular 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 predominant 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 noncholinergic (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 presynaptic receptors of the non-adrenergic non-cholinergic (NANC) nerves preventing release of inflammatory neuropeptides such as substance P and neurokinin A.

Effect of the two tachykinin antagonists, SR 48968 and SR 140333, on cough induced by citric acid in the unanaesthetized guinea pig

“…doses that were considerably higher than those which exerted bronchodilator effects in the guinea-pig. The effective dose producing 50% inhibition (ED50) of the bronchodilator effect of salbutamol versus histamine is 0.6 µg·kg -1 [30]. Consequently, we have pretreated animals with salbutamol at a dose (0.3 mg·kg -1 ) which is not antitussive, but presents marked bronchodilator effects.…”

The Difference in Citric Acid-Induced Cough in Congenitally Bronchial-Hypersensitive (BHS) and Bronchial-Hyposensitive (BHR) Guinea Pigs.

“…Intravenous administration of salbutamol, a β 2 agonist known as a potent bronchodilator, inhibited the increase of pulmonary airway resistance induced by histamine or bradykinin in guinea pigs [1], and also the inhalation of salbutamol inhibited the bronchoconstriction induced by histamine aerosols [24]. In the present study, pretreatment with salbutamol aerosol significantly decreased the number of coughs and increased the latency to cough induced by citric acid in both strains of guinea pigs; the number of coughs showed an 89.4% decrease in BHS and an 85.8% decrease in BHR compared to vehicle challenge, and the latency to cough was showed a 140.1% increase in BHS and a 69.4% increase in BHR compared to vehicle challenge.…”

Inhibition by fenoterol of human eosinophil functions includingβ2-adrenoceptor-independent actions

“…Such agonists also were shown to decrease reactivity and effects of inflammatory cells. These drugs can inhibit mast cell degranulation [16], early and late cutaneous reactions to antigen as well as certain other allergic reactions [17 , 18], plasma leakage in response to various inflammatory stimuli [19][20][21], oxidant production [22][23][24][25] and LTC4 production [26].…”