EFFECTS OF TOXINS, APAMINE, CHARYBDOTOXIN AND IBERIOTOXIN ON THE SMOOTH-MUSCLE RELAXANT ACTIVITY OF AN IMIDAZO (1,2-A)PYRAZINE DERIVATIVE

Experiments have been performed in order to analyse the mechanism wher eby SCA40, a new imidazo[1,2-a]pyrazine derivative relaxes airway smoo th muscle. We investigated the effect of different toxins, known to be K+-channel blockers on guinea-pig smooth muscle relaxant activity of SCA40. The small conductance Ca2+-activated K+-channel blocker apamin (100 nM) did not antagonize the relaxant activity of SCA40 in 1 muM ca rbachol-contracted isolated guinea pig trachea. The large conductance Ca2+-activated K+-channel blocker, iberiotoxin (30, 60 and 180 nM) ant agonized the relaxant activity of SCA40 in an apparently competitive m anner. The concentration-relaxation curves to SCA40 were shifted to th e right with no significant alteration in the maximum response. The re laxant activity of SCA40 in 1 muM carbachol-contracted isolated trache a was antagonized by both charybdotoxin (60 nM) and iberiotoxin (60 nM ), but the antagonism induced by iberiotoxin appears to be more potent than that induced by charybdotoxin. It is concluded that the potent r elaxant activity of SCA40 on guinea-pig airway smooth muscle in vitro involves a charybdotoxin and iberiotoxin sensitive K+-channel.