Effect of YM934, a KATP channel opener, on airway hyperresponsiveness induced by platelet activating factor in guinea-pigs

Abstract

The effect of YM934 (2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1, 4-benzoxazin-4-yl)pyridine N-oxide) on airway hyperresponsiveness induced by platelet activating factor (PAF) was investigated in anesthetized guinea-pigs. Bronchoconstrictor responses to histamine were enhanced by intravenous (i.v.) infusion of PAF (600 ng/kg/h for 1 h). The KATP channel opener, YM934 (10-100 micrograms/ kg), given by i.v. bolus injection or i.v. infusion (75 min) dose-dependently inhibited this PAF-induced airway hyperresponsiveness. In the normal control group, i.v. bolus injection of YM934 dose-dependently reduced the bronchoconstrictor responses to histamine. However, i.v. infusion of YM934 (100 micrograms/kg) had almost no effect on responsiveness. Pretreatment with capsaicin (50 micrograms/kg, s.c.), a depleter of neuropeptides, partially prevented the development of PAF-induced airway hyperresponsiveness. In contrast, phosphoramidon (2.5 mg/kg, i.v.), an inhibitor of neutral endopeptidase, enhanced the airway hyperresponsiveness induced by PAF. Furthermore, YM934 inhibited PAF-induced airway hyperresponsiveness in guinea-pigs pretreated with capsaicin or phosphoramidon. The present results suggest that YM934 given by i.v. infusion reduces PAF-induced airway hyperresponsiveness at doses insufficient to produce a bronchodilatory effect. Further, the mechanism of YM934's inhibitory effect on airway hyperresponsiveness may involve bronchodilatory and other unidentified effects, such as a decrease in the release of neuropeptides from sensory nerve terminals.

From Cromakalim to Different Structural Classes of KATP Channel Openers

“…The 12)] which is a potent vasodilator, that is 3-times more potent than LCRK, with particularly pronounced effect on coronary artery [92]. YM-934 (52) has been extensively evaluated in an attempt to delineate its pharmacological profile on cardiovascular [93][94][95], respiratory [96,97], and urinary [98,99] systems. A recent article by Astellas Pharmaceutical confirmed that a non-hypotensive dose of YM-934 significantly decreased coronary peripheral vascular resistances, increased coronary flow and enhanced myocardial recovery from transient coronary flow interruption in a dog model of impaired coronary circulation similar to unstable angina [100].…”