Saitoh C, Ishikawa J, Asano M
Clinical Pharmacology Research Laboratories, Yamanouchi Pharmaceutical Co., Ltd., Tokyo, Japan.
Naunyn Schmiedebergs Arch Pharmacol. 1997 Feb;355(2):203-9. doi: 10.1007/pl00004933.
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.
在麻醉的豚鼠中研究了YM934（2-(3,4-二氢-2,2-二甲基-6-硝基-2H-1,4-苯并恶嗪-4-基)吡啶N-氧化物）对血小板活化因子（PAF）诱导的气道高反应性的影响。静脉输注PAF（600 ng/kg/h，持续1小时）可增强对组胺的支气管收缩反应。静脉推注或静脉输注（75分钟）KATP通道开放剂YM934（10 - 100微克/千克）剂量依赖性地抑制这种PAF诱导的气道高反应性。在正常对照组中，静脉推注YM934剂量依赖性地降低对组胺的支气管收缩反应。然而，静脉输注YM934（100微克/千克）对反应性几乎没有影响。用辣椒素（50微克/千克，皮下注射）预处理，一种神经肽耗竭剂，部分预防了PAF诱导的气道高反应性的发展。相反，中性内肽酶抑制剂磷酰胺（2.5毫克/千克，静脉注射）增强了PAF诱导的气道高反应性。此外，YM934在经辣椒素或磷酰胺预处理的豚鼠中抑制PAF诱导的气道高反应性。目前的结果表明，静脉输注YM934在不足以产生支气管扩张作用的剂量下可降低PAF诱导的气道高反应性。此外，YM934对气道高反应性的抑制作用机制可能涉及支气管扩张和其他未确定的作用，例如感觉神经末梢神经肽释放的减少。
