Effect of YM934, a Novel K+-channel Opener, on Non-adrenergic Non-cholinergic Neural Bronchoconstriction in Guinea-pigs

The effect of YM934 (2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4-yl)pyridine N-oxide) on non-adrenergic non-cholinergic (NANC) neural bronchoconstriction was investigated in anaesthetized guinea-pigs, and compared with that of levcromakalim. After pre-treatment with atropine (1 mg kg−1, i.v.) and propranolol (1 mg kg−1, i.v.), bilateral vagal stimulation evoked a NANC neural bronchoconstriction. YM934 (10–100 μg kg−1, i.v.) and levcromakalim (30–300 μg kg−1, i.v.) dose-dependently inhibited the increase in airway resistance evoked by vagal stimulation with ED50 values of 55·7 and 113·4 μg kg−1, i.v., respectively. The effect of YM934 was about twice as potent as that of levcromakalim. The inhibitory effect of YM934 was antagonized by glibenclamide (25 mg kg−1, i.v.), an ATP-sensitive K+-channel blocker. YM934 (100 μg kg−1, i.v.) had no inhibitory effect on exogenous substance P- (20 μg kg−1, i.v.) or neurokinin A- (1–1·5 μg kg−1, i.v.) induced bronchoconstriction. These results suggest that YM934 has a potent inhibitory effect on NANC neural bronchoconstriction by reducing the release of neuropeptides from sensory nerve terminals, and that the action of YM934 is mainly attributable to its ATP-sensitive K+-channel opening activity.