IN-VITRO AND IN-VIVO EFFECTS OF SCA40 ON GUINEA-PIG AIRWAYS

SCA40 methylaminoimidazo[1,2-a]pyrazine-2-carbonitrile), a compound wh ich had been described as an opener of Ca2+-dependent large conductanc e potassium channels (BKCa channels), was investigated in comparison w ith salbutamol for in vitro and in vivo bronchospasmolytic effects and for the ability to reverse airways hyperreactivity in guinea pigs. SC A40 reduced the spontaneous tone of isolated guinea pig tracheal rings with a biphasic concentration-response curve (first phase: pD(2) = 8. 0, E(Max) = 29.7% of maximal effect; second phase: pD(2) = 6.4, E(Max) = 72.6%). The salbutamol curve was monophasic (pD(2) = 8.0, E(Max) = 100%). Total lung resistance (R(L)) was determined in anaesthetized, v entilated guinea pigs. Bronchoconstriction, measured as an increase in R(L), was elicited in normoreactive animals by i.v. infusion of bombe sin (100 ng/kg/min) or by i.v. injection of histamine (1.8-5.6 mu g/kg ). Airways hyperreactivity was induced by acute i.v. administration of pre-formed immune complexes. Intravenous bolus injections of histamin e (2.4 mu g/kg) were used to define the sensitivity of the airways pri or to and after the exposure to immune complex. Following intratrachea l (i.t.) administration, SCA40 reversed bombesin-induced bronchoconstr iction with an ED(50) of 43 mu g/kg (E(Max) = 57%). The ED(50) for sal butamol was 0.8 mu g/kg i.t. (E(Max) = 78%). Histamine-induced broncho constriction in hyperreactive guinea pigs was inhibited by SCA40 with an ED(50) of 13 mu g/kg i.t. (E(Max) = 82%). Salbutamol completely inh ibited histamine-induced bronchospasm with an ED(50) of 9 ng/kg i.t. I n normoreactive guinea pigs, SCA40 prevented histamine-induced broncho constriction with an ED(50) of 100 mu g/kg i.t.; for salbutamol the ED (50) in this test was 0.48 mu g/kg i.t. Thus, for both SCA40 and salbu tamol, the effects obtained at low doses in hyperreactive guinea pigs represent a true reversal of airways hyperreactivity, whereas at highe r doses, anti-hyperreactive and bronchospasmolytic properties may acco unt for the observed effects. In conclusion, SCA40 relaxes guinea pig airways smooth muscle in vitro and in vivo, and it partly reverses air ways hyperreactivity. With respect to both potency and efficacy, SCA40 is markedly less active than the beta-adrenoceptor agonist salbutamol .