EFFECTS OF SCA40 ON HUMAN BRONCHI AND ON GUINEA-PIG MAIN BRONCHI IN-VITRO - COMPARISON WITH CROMAKALIM

The aim of this study was to examine the activity of SCA40, a novel ch arybdotoxin-sensitive potassium channel opener, against a variety of s pasmogens or against electrical field stimulation in guinea pig isolat ed main bronchi and in human isolated bronchi; the effects of SCA40 we re compared with those of cromakalim. Like cromakalim, SCA40 reduced t he contractility of guinea pig and human isolated bronchi precontracte d with acetylcholine 10(-6) M or neurokinin A 10(-6) M, SCA40 being mo re efficient and more potent than cromakalim. Moreover, on guinea pig isolated main bronchi, SCA40 can exert a preventive effect on contract ions induced by acetylcholine, neurokinin A or capsaicin, that is, it shifts to the right the concentration-effect curves of these substance s, whereas cromakalim has no such effect. The effects of cromakalim we re antagonized by glibenclamide 10(-5) M, whereas the effects of SCA40 were inhibited by tetraethylammonium (TEA 10(-2) M) and charybdotoxin (3 x 10(-8) M), but this inhibitory effect of TEA was reversed by nif edipine (10(-6) M). Electrical field stimulation of guinea pig isolate d main bronchi induced two successive contractile responses. Both cont ractions were significantly reduced by SCA40 (10(-6) and 10(-5) M) and cromakalim (10(-5) M). Since cromakalim was unable to inhibit the eff ects of acetylcholine or neurokinin A, it might be suggested that for this latter compound the inhibition seems to take place prejunctionall y and to affect the release of neuromediators produced by electrical f ield stimulation. In contrast, in the case of SCA40, a postjunctional effect seems to be likely, owing to its preventive effects, although a prejunctional effect cannot be excluded. Finally, on guinea pig isola ted main bronchi, SCA40 (10(-8)-10(-6) M) did not potentiate the relax ant effect of isoprenaline or sodium nitroprusside, suggesting a lack of functional manifestation of inhibition of phosphodiesterase for the se concentrations. In conclusion, these results demonstrate that SCA40 is a potent and efficient relaxant of guinea pig and human ah-way smo oth muscle, and is able to inhibit, in the guinea pig isolated main br onchi, the contractions induced by electrical field stimulation. It ha s an effect on TEA-sensitive K+ channels, but this effect is probably not involved in its relaxant effect which does not also rest on an inh ibitory effect of phosphodiesterase.