Antitussive effect of NS-398, a selective cyclooxygenase-2 inhibitor, in guinea pigs.
Antitussive effect of NS-398, a selective cyclooxygenase-2 inhibitor, in guinea pigs.
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NS-398（一种选择性环氧合酶 2 抑制剂）对豚鼠的镇咳作用。
DOI：
10.1016/j.ejphar.2004.06.045
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发表时间：
2004
影响因子：
5
通讯作者：
A. Saitoh
中科院分区：
文献类型：
--
作者：
J. Kamei;Yasuhiro Matsunawa;A. Saitoh
一些报告表明，当呼吸道中存在前列腺素时，辣椒素诱导的咳嗽次数会增加。此外，有报道称，在培养的人呼吸道上皮细胞中，在没有炎性细胞因子刺激的情况下，发现了环氧合酶-2的表达，该酶能将花生四烯酸转化为前列腺素。因此，环氧合酶-2抑制剂有可能产生镇咳作用。为了验证这一假说，我们观察了选择性环氧合酶-2抑制剂N-[2-(环己氧基)-4-硝基苯基]-甲烷磺胺(NS-398)和选择性环氧合酶-1抑制剂5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethyl-pyrazole(SC-560)对辣椒素诱发豚鼠咳嗽的影响。NS-398(1-10 mg/kg，P.O.)剂量依赖性地显著减少辣椒素诱导的咳嗽次数。而SC-560(10 mg/kg，P.O.)并未减少辣椒素引起的咳嗽次数。NS-398(10 mg/kg，P.O.)的镇咳作用非选择性5-羟色胺(5-羟色胺)受体拮抗剂甲基丝氨酸(3 mg/kg)或ATP敏感性钾通道阻断剂格列本脲(10 mg/kg)不能拮抗上述作用。此外，NS-398对P物质(10-16M)引起的咳嗽反射无明显影响，但可显著减少辣椒素诱导的支气管肺泡灌洗液(BALF)中P物质的释放。目前的研究结果清楚地表明，环氧合酶-2抑制剂，而不是环氧合酶-1抑制剂，具有很强的镇咳作用。此外，NS-398的镇咳作用可能不依赖于中枢作用机制，因为5-羟色胺受体在中枢镇咳药物的镇咳作用中起着重要作用。NS-398可能通过抑制呼吸道辣椒素敏感传入C纤维中P物质的释放而发挥外周镇咳作用。这些结果表明，环氧合酶-2抑制剂可能在减少咳嗽方面有治疗作用。
Several reports have demonstrated that the number of capsaicin-induced coughs is increased in the presence of prostaglandins in the airway. Moreover, it has been reported that the expression of cyclooxygenase-2, which converts arachidonic acid to prostaglandins, was found in cultured human airway epithelial cells in the absence of inflammatory cytokine stimulation. Thus, it is possible that cyclooxygenase-2 inhibitor may produce an antitussive effect. To test this hypothesis, we investigated the effects of N-[2-(cyclohexyloxy)-4-nitrofenyl]-methane sulfonamide (NS-398), a selective cyclooxygenase-2 inhibitor, and 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethyl-pyrazole (SC-560), a selective cyclooxygenase-1 inhibitor, on capsaicin-induced coughs in guinea pigs. NS-398 (1–10 mg/kg, p.o.) dose-dependently and significantly reduced the number of capsaicin-induced coughs. In contrast, SC-560 (10 mg/kg, p.o.) did not reduce the number of capsaicin-induced coughs. The antitussive effect of NS-398 (10 mg/kg, p.o.) was not antagonized by pretreatment with methysergide (3 mg/kg, i.p.), a non-selective serotonin (5-HT) receptor antagonist, or glibenclamide (10 mg/kg, i.p.), an ATP-sensitive K+channel blocker. Furthermore, although NS-398 did not significantly affect the cough reflex induced by substance P (10-16M), it significantly reduced the capsaicin-induced release of substance P in bronchoalveolar lavage fluid (BALF). The present findings clearly show that cyclooxygenase-2 inhibitor, but not cyclooxygenasez-1 inhibitor, has a potent antitussive effect. Furthermore, it is possible that the antitussive action of NS-398 does not depend on centrally acting mechanisms, since 5-HT receptors play an important role in the cough-depressant activities of centrally acting antitussive drugs. NS-398 may exert peripheral antitussive effects by inhibiting the release of substance P from capsaicin-sensitive afferent C-fibers in the airways. These results suggest that cyclooxygenase-2 inhibitors may have a therapeutic benefit in reducing coughs.
DOI：
10.1183/09031936.98.11020339
发表时间：
1998-02
期刊：
The European respiratory journal
影响因子：
--
作者：
G. Sant'ambrogio;F. Sant'ambrogio
通讯作者：
G. Sant'ambrogio;F. Sant'ambrogio