FORMOTEROL AND SALBUTAMOL INHIBIT BRADYKININ-INDUCED AND HISTAMINE-INDUCED AIRWAY MICROVASCULAR LEAKAGE IN GUINEA-PIG

1 The effects of the beta(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)-mu-g kg-1 respectively for salbutamol, and 0.13 +/- 0.12 (n = 6) and 0.02 +/- 0.01 (n = 6)-mu-g kg-1 respectively for formoterol. 3 Salbutamol (10 and 30-mu-g kg-1) and formoterol (1 and 10-mu-g kg-1) inhibited the increase of microvascular permeability induced by histamine (30-mu-g kg-1) 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 10-mu-g kg-1) abolished the increase in microvascular permeability induced by bradykinin (0.3-mu-g kg-1). This inhibitory effect of two beta-adrenoceptor stimulants was predominant in the trachea and the nasal mucosa where it was observed with 1-mu-g kg-1 of the beta-adrenoceptor agonists. In the main bronchi, and in the proximal and distal intrapulmonary airways, the effects of bradykinin were abolished by 10-mu-g kg-1 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 10 mg kg-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 beta-adrenoceptor stimulants can inhibit, partially or totally, the increase or 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 beta(2)-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.