Roles of stretch-activated cation channel and Rho-kinase in the spontaneous contraction of airway smooth muscle

Satoru Ito, Hiroaki Kume, Tetsuya Oguma, Yasushi Ito, Masashi Kondo, Kaoru Shimokata, Béla Suki, Keiji Naruse

研究成果: Article査読

32 被引用数 (Scopus)

抄録

In guinea pigs, it is well-known that mechanical stretch of airway smooth muscle exhibits spontaneous tone which is mediated by cyclooxygenase (COX) activation. We tested the hypothesis that this spontaneous contraction of airway smooth muscle is mediated by stretch-activated non-selective cation channels and the Rho/Rho-kinase pathway, as well as COX-2 using a pharmacological approach. Isometric force and intracellular Ca2+ concentrations ([Ca2+]i) were assessed in isolated guinea pig tracheal smooth muscle tissues. The samples were stretched to a given level and the muscle behavior was monitored under isometric conditions. We observed an increase in [Ca2+]i and subsequent force generation over a 15-min period. The augmented [Ca2+]i and spontaneous contraction due to the stretch were markedly attenuated by application of Gd3+, an inhibitor of stretch-activated channels, and removal of extracellular Ca2+. In contrast, nifedipine only had a mild inhibitory effect on the contraction. (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexane-carboxamide (Y-27632; a Rho-kinase inhibitor) abolished the spontaneous contraction with no changes in [Ca2+]i. Simvastatin, which down-regulates Rho activity, also significantly inhibited the contraction. Moreover, indomethacin, an inhibitor of COX-1 and -2, and N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (NS-398; a COX-2 inhibitor) abolished the stretch-induced contraction without affecting [Ca2+]i, whereas the inhibitory effect of 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (SC560; a COX-1 inhibitor) on the contraction was much less. These findings demonstrated that Ca2+ entry via stretch-activated channels, the Rho/Rho-kinase pathway, and COX-2 are involved in the mechanotransduction in guinea pig tracheal smooth muscle. Additionally, while the Rho/Rho-kinase pathway and COX-2 regulate the spontaneous contraction independently of [Ca2+]i, COX-1 is not involved in the stretch-induced force generation.

本文言語English
ページ(範囲)135-142
ページ数8
ジャーナルEuropean Journal of Pharmacology
552
1-3
DOI
出版ステータスPublished - 15-12-2006
外部発表はい

All Science Journal Classification (ASJC) codes

  • 薬理学

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