EVALUATION OF THE RELAXANT EFFECTS OF SCA40, A NOVEL CHARYBDOTOXIN-SENSITIVE POTASSIUM CHANNEL OPENER, IN GUINEA-PIG ISOLATED TRACHEALIS

1 Experiments have been performed in order to analyse the mechanism whereby SCA40, a new imidazo[1,2-a]pyrazine derivative relaxes airway smooth muscle. 2 SCA40 (0.01-10 muM) caused a complete and concentration-dependent relaxation of guinea-pig isolated trachea contracted with 20 mm KCl but failed to inhibit completely the spasmogenic effects of 80 mm KCl. 3 Quinine (30 muM) antagonized the relaxant activity of SCA40 in 20 mm KCI-contracted guinea-pig isolated trachea. The ATP-sensitive K+-channel blocker, glibenclamide (3 muM), did not antagonize the relaxant activity of SCA40 in either 20 mm KCI or 1 muM carbachol-contracted isolated trachea. 4 SCA40 (0.01 - 10 muM) and isoprenaline (0.1 nm - 10 muM) caused a complete and concentration-dependent relaxation of guinea-pig isolated trachea contracted with carbachol 1 muM. 5 The large-conductance Ca2+-activated K+-channel blocker, charybdotoxin (60- 180 nm), non-competitively antagonized the relaxant activity of isoprenaline on 1 muM carbachol-contracted trachea. The inhibition was characterized by rightward shifts of the isoprenaline concentration-relaxation curves with depression of their maxima. 6 The relaxant activity of SCA40 in 1 muM carbachol-contracted trachea was antagonized by charybdotoxin (60-600 nm) in an apparently competitive manner. The concentration-relaxation curves to SCA40 were shifted to the right with no significant alteration in the maximum response. 7 It is concluded that SCA40 is a novel potassium channel opener which is a potent relaxant of guinea-pig airway smooth muscle in vitro. The relaxant activity of SCA40 does not involve ATP-sensitive K+-channels but rather large-conductance Ca2+-activated K+-channels or other charybdotoxin-sensitive K+-channels.