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 for moterol, on the increase of microvascular permeability induced by hist amine or bradykinin in guinea-pig airways have been studied in vivo. E xtravasation of intravenously injected Evans blue dye was used as an i ndex of permeability. The effects of salbutamol and formoterol on the increase in pulmonary airway resistance induced by histamine or bradyk inin have also been studied. 2 The increase in pulmonary airway resist ance induced by histamine or bradykinin was totally inhibited by salbu tamol 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 salbutam ol, and 0.13 +/- 0.12 (n = 6) and 0.02 +/- 0.01 (n = 6)-mu-g kg-1 resp ectively for formoterol. 3 Salbutamol (10 and 30-mu-g kg-1) and formot erol (1 and 10-mu-g kg-1) inhibited the increase of microvascular perm eability induced by histamine (30-mu-g kg-1) in the guinea-pig airways . The inhibitory effect was predominant in the trachea and the main br onchi, with a maximum inhibition of 20 to 50%. The two drugs had littl e or no inhibitory effect on the other structures studied, viz. nasal mucosa, larynx, proximal and distal intrapulmonary airways. 4 Salbutam ol and formoterol (1 and 10-mu-g kg-1) abolished the increase in micro vascular permeability induced by bradykinin (0.3-mu-g kg-1). This inhi bitory effect of two beta-adrenoceptor stimulants was predominant in t he 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 pr oximal and distal intrapulmonary airways, the effects of bradykinin we re abolished by 10-mu-g kg-1 of formoterol and salbutamol. 5 The effec ts of bradykinin, but not those of histamine, were significantly reduc ed (nasal mucosa, main bronchi and distal intrapulmonary airways) or a bolished (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, intrave nously injected beta-adrenoceptor stimulants can inhibit, partially or totally, the increase or airways microvascular permeability induced b y intravenous histamine or bradykinin. However, these effects require doses that are higher than those that inhibit the increase in pulmonar y airway resistance induced by these mediators. As suggested by the re sults obtained with morphine, the higher efficacy of beta(2)-adrenocep tor agonists versus bradykinin may occur through activation of presyna ptic receptors of the non-adrenergic non-cholinergic (NANC) nerves pre venting release of inflammatory neuropeptides such as substance P and neurokinin A.