KATP channel openers reverse immune complex-induced airways hyperreactivity independently of smooth muscle relaxation

Many openers of ATP-dependent potassium channels (KATP channel openers) cause bronchorelaxation, whereas only a few of them have been claimed to reverse airways hyperreactivity. We investigated whether the antihyperreactive effect is a general feature of KATP channel openers and whether this property is linked to their ability to relax airways smooth muscle. For this purpose, the potency of the four KATP channel openers, bimakalim, rilmakalim, levcromakalim and SDZ PCO 400 ((-)-(3S,4R)-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(3-oxo-cyclopent -1 -enyloxy)-2H-1-benzopyran-6-carbonitrile), to inhibit bombesin- or histamine-induced bronchoconstriction and to reverse immune complex-induced airways hyperreactivity to histamine in guinea pigs, was compared to salbutamol, following intratracheal administration to minimize pharmacokinetic differences. Total lung resistance (RL) was determined in anaesthetized, ventilated guinea pigs. Bronchoconstriction, measured as increase in RL, was elicited in normoreactive animals by i.v. infusion of bombesin (100 ng/kg/min) or by i.v. injection of histamine (1.8-10 micrograms/kg). Airways hyper-reactivity was induced by acute i.v. administration of preformed immune complexes. I.v. bolus injections of histamine were used to define the sensitivity of the airways prior to and after the exposure to immune complex. Levcromakalim (ED50 = 150 micrograms/kg), bimakalim (ED50 = 4 micrograms/kg), rilmakalim (ED50 = 40 micrograms/kg) and SDZ PCO 400 (ED50 = 280 micrograms/kg) reverse bombesin-induced bronchoconstriction with lower potency than salbutamol (ED50 = 1 microgram/kg). The four KATP channel openers and salbutamol also reversed immune complex-induced airways hyperreactivity to histamine with ED50 values which were markedly lower than those for reversal of bombesin-induced bronchoconstriction; the rank order of potency was rilmakalim (ED50 = 0.2 microgram/kg) > bimakalim (ED50 = 0.5 microgram/kg) > SDZ PCO 400 (ED50 = 3.2 micrograms/kg) > levcromakalim (ED50 = 22 micrograms/kg). Salbutamol (ED50 = 0.008 microgram/kg) was the most potent compound in this test. Bimakalim, levcromakalim and SDZ PCO 400 did not inhibit histamine-induced bronchoconstriction in normoreactive guinea pigs at doses which completely reversed immune complex-induced airways hyperreactivity to histamine. 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 hyperreactivity. There was a poor correlation between the ED50 values for inhibition of histamine- or bombesin-induced bronchoconstriction in normoreactive guinea pigs and the reversal of immune complex-induced airways hyperreactivity. It is thus concluded that the ability of KATP channel openers to reverse immune complex-induced airways hyperreactivity is independent of their ability to reverse or prevent bronchoconstriction and thus from their ability relax airway smooth muscle.