EFFECTS OF CROMAKALIM ON BRADYKININ-INDUCED, HISTAMINE-INDUCED AND SUBSTANCE-P-INDUCED AIRWAY MICROVASCULAR LEAKAGE IN THE GUINEA-PIG

The effects of cromakalim on the increase in microvascular permeability induced by histamine, substance P or bradykinin in guinea-pig airways were studied in vivo. Extravasation of i.v. injected Evans blue dye was used as an index of permeability. We also studied the effects of cromakalim on the contractile effect of substance P, histamine or bradykinin on the isolated guinea-pig main bronchus and on the contractile response of isolated guinea-pig main bronchi to electrical field stimulation. Cromakalim (30 to 300 mug.kg-1) did not inhibit the increase in microvascular permeability induced by histamine (30 mug.kg-1) in guinea-pig airways and potentiated (30 and 100 mug.kg-1) the effects of substance P (0.3 mug.kg-1) in trachea, main bronchi and proximal intrapulmonary airways. In contrast, cromakalim (30 and 300 mug.kg-1) reduced the increase in microvascular permeability induced by bradykinin (0.3 mug.kg-1). However, a significant potentiation of the effects of bradykinin was observed with cromakalim (100 mug.kg-1) in main bronchi and intrapulmonary airways. In the isolated guinea-pig main bronchus, the contractile effects of bradykinin, histamine and substance P were not modified by cromakalim (10(-5) M). Conversely, cromakalim (10(-5) M) significantly reduced both cholinergic and noncholinergic contractile responses induced by electrical field stimulation of the isolated guinea-pig main bronchus. In conclusion, cromakalim can partially inhibit the increase in microvascular permeability induced by i.v. bradykinin. It is suggested that this effect might occur through inhibition of the nonadrenergic noncholinergic excitatory (NANC) nerves preventing release by bradykinin of inflammatory neuropeptides such as substance P.