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

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)135-142
Number of pages8
JournalEuropean Journal of Pharmacology
Volume552
Issue number1-3
DOIs
Publication statusPublished - 15-12-2006

Fingerprint

rho-Associated Kinases
Cyclooxygenase 2
Cyclooxygenase 1
Smooth Muscle
Cations
Guinea Pigs
Muscles
Simvastatin
Cyclooxygenase Inhibitors
Cyclooxygenase 2 Inhibitors
Nifedipine
Prostaglandin-Endoperoxide Synthases
Indomethacin
Down-Regulation
Pharmacology
N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Ito, Satoru ; Kume, Hiroaki ; Oguma, Tetsuya ; Ito, Yasushi ; Kondo, Masashi ; Shimokata, Kaoru ; Suki, Béla ; Naruse, Keiji. / Roles of stretch-activated cation channel and Rho-kinase in the spontaneous contraction of airway smooth muscle. In: European Journal of Pharmacology. 2006 ; Vol. 552, No. 1-3. pp. 135-142.
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Roles of stretch-activated cation channel and Rho-kinase in the spontaneous contraction of airway smooth muscle. / Ito, Satoru; Kume, Hiroaki; Oguma, Tetsuya; Ito, Yasushi; Kondo, Masashi; Shimokata, Kaoru; Suki, Béla; Naruse, Keiji.

In: European Journal of Pharmacology, Vol. 552, No. 1-3, 15.12.2006, p. 135-142.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Roles of stretch-activated cation channel and Rho-kinase in the spontaneous contraction of airway smooth muscle

AU - Ito, Satoru

AU - Kume, Hiroaki

AU - Oguma, Tetsuya

AU - Ito, Yasushi

AU - Kondo, Masashi

AU - Shimokata, Kaoru

AU - Suki, Béla

AU - Naruse, Keiji

PY - 2006/12/15

Y1 - 2006/12/15

N2 - 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.

AB - 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.

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