Antitussive effect of NS-398, a selective cyclooxygenase-2 inhibitor, in guinea pigs.
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(-16) M), 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.
Department of Pathophysiology and Therapeutics, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 4-41, Ebara 2-chome, Shinagawa-ku, Tokyo 142-8501, Japan. kamei@hoshi.ac.jp
Junzo
J
Kamei
Yasuhiro
Y
Matsunawa
Akiyoshi
A
Saitoh
D000818:Animals; D000996:Antitussive Agents / Q000627:therapeutic use*; D003371:Cough / Q000188:drug therapy* / Q000201:enzymology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D008297:Male; D009578:Nitrobenzenes / Q000627:therapeutic use*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D013449:Sulfonamides / Q000627:therapeutic use*
D000996:Antitussive Agents; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases