EFFECT OF YM934, A K-ATP CHANNEL OPENER, ON AIRWAY HYPERRESPONSIVENESS INDUCED BY PLATELET-ACTIVATING-FACTOR IN GUINEA-PIGS

The effect of YM934 (2-(3,4-dihydro-2,2-dimethyl-6-nitro-2 H-1,4-benzo xazin-4-yl)pyridine N-oxide) on airway hyperresponsiveness induced by platelet activating factor (PAF) was investigated in anesthetized guin ea-pigs. Bronchoconstrictor responses to histamine were enhanced by in travenous (i.v.) infusion of PAF (600 ng/kg/h for 1 h). The K-ATP chan nel opener, YM934 (10-100 mu g/kg), given by i.v. bolus injection or i .v. infusion (75 min) dose-dependently inhibited this PAF-induced airw ay hyperresponsiveness. In the normal control group, i.v. bolus inject ion of YM934 dose-dependently reduced the bronchoconstrictor responses to histamine. However, i.v. infusion of YM934 (100 mu g/kg) had almos t no effect on responsiveness. Pretreatment with capsaicin (50 mg/kg, s.c.), a depleter of neuropeptides, partially prevented the developmen t of PAF-induced airway hyperresponsiveness. In contrast, phosphoramid on (2.5 mg/kg, i.v.), an inhibitor of neutral endopeptidase, enhanced the airway hyperresponsiveness induced by PAF. Furthermore, YM934 inhi bited PAF-induced airway hyperresponsiveness in guinea-pigs pretreated with capsaicin or phosphoramidon. The present results suggest that YM 934 given by i.v. infusion reduces PAF-induced airway hyperresponsiven ess at doses insufficient to produce a bronchodilatory effect. Further , the mechanism of YM934's inhibitory effect on airway hyperresponsive ness may involve bronchodilatory and other unidentified effects, such as a decrease in the release of neuropeptides from sensory nerve termi nals.