Evaluation of the relaxant effects of SCA40, a novel charybdotoxin‐sensitive potassium channel opener, in guinea‐pig isolated trachealis

Abstract

1 Experiments have been performed in order to analyse the mechanism whereby SCA40, a new imidazo[1,2-α]pyrazine derivative relaxes airway smooth muscle. 2 SCA40 (0.01–10 μm) 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 μm) antagonized the relaxant activity of SCA40 in 20 mm KCl-contracted guinea-pig isolated trachea. The ATP-sensitive K⁺-channel blocker, glibenclamide (3 μm), did not antagonize the relaxant activity of SCA40 in either 20 mm KCl or 1 μm carbachol-contracted isolated trachea. 4 SCA40 (0.01–10 μm) and isoprenaline (0.1 nm-10 μm) caused a complete and concentration-dependent relaxation of guinea-pig isolated trachea contracted with carbachol 1 μm. 5 The large-conductance Ca²⁺-activated K⁺-channel blocker, charybdotoxin (60–180 nm), non-competitively antagonized the relaxant activity of isoprenaline on 1 μm 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 μm 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.