K-ATP CHANNEL OPENERS REVERSE IMMUNE COMPLEX-INDUCED AIRWAYS HYPERREACTIVITY INDEPENDENTLY OF SMOOTH-MUSCLE RELAXATION

Many openers of ATP-dependent potassium channels (K-ATP channel opener s) cause bronchorelaxation, whereas only a few of them have been claim ed to reverse airways hyperreactivity. We investigated whether the ant i-hyperreactive effect is a general feature of K-ATP channel openers a nd whether this property is linked to their ability to relax airways s mooth muscle. For this purpose, the potency of the four K-ATP channel openers, bimakalim, rilmakalim, levcromakalim and SDZ PCO 400 hyl-4-(3 -enyloxy)-2H-1-benzopyran-6-carbonitrile), to inhibit bombesin- or his tamine-induced bronchoconstriction and to reverse immune complex-induc ed airways hyperreactivity to histamine in guinea pigs, was compared t o salbutamol, following intratracheal administration to minimize pharm acokinetic differences. Total lung resistance (R(L)) was determined in anaesthetized, ventilated guinea pigs. Bronchoconstriction, measured as increase in R(L), was elicited in normoreactive animals by i.v. inf usion of bombesin (100 ng/kg/min) or by i.v. injection of histamine (1 .8-10 mu g/kg). Airways hyperreactivity was induced by acute i.v. admi nistration of pre formed immune complexes. Lv. bolus injections of his tamine were used to define the sensitivity of the airways prior to and after the exposure to immune complex. Levcromakalim (ED(50) = 150 mu g/kg), bimakalim (ED(50) = 4 mu g/kg), rilmakalim (ED(50) = 40 mu g/kg ) and SDZ PCO 400 (ED(50) = 280 mu g/kg) reversed bombesin-induced bro nchoconstriction with lower potency than salbutamol (ED(50) = 1 mu g/k g). The four K-ATP channel openers and salbutamol also reversed immune complex-induced airways hyperreactivity to histamine with ED(50) valu es which were markedly lower than those for reversal of bombesin-induc ed bronchoconstriction; the rank order of potency was rilmakalim (ED(5 0) = 0.2 mu g/kg) > bimakalim (ED(50) = 0.5 mu g/kg) > SDZ PCO 400 (ED (50) = 3.2 mu g/kg) > levcromakalim (ED(50) = 22 mu g/kg). Salbutamol (ED(50) = 0.008 mu g/kg) was the most potent compound in this test. Bi makalim, levcromakalim and SDZ PCO 400 did not inhibit histamine-induc ed bronchoconstriction in normoreactive guinea pigs at doses which com pletely reversed immune complex-induced airways hyperreactivity to his tamine. For rilmakalim and salbutamol, 60-130 times higher doses were needed for protection against histamine-induced bronchoconstriction in normoreactive guinea pigs than for reversal of airways hyperreactivit y. There was a poor correlation between the ED(50) values for inhibiti on of histamine- or bombesin-induced bronchoconstriction in normoreact ive guinea pigs and the reversal of immune complex-induced airways hyp erreactivity. It is thus concluded that the ability of K-ATP channel o peners to reverse immune complex-induced airways hyperreactivity is in dependent of their ability to reverse or prevent bronchoconstriction a nd thus from their ability relax airway smooth muscle.