Direct effects of hydrogen peroxide on airway smooth muscle tone: Roles of Ca2+ influx and Rho-kinase

Katsuyuki Kojima, Hiroaki Kume, Satoru Ito, Tetsuya Oguma, Akira Shiraki, Masashi Kondo, Yasushi Ito, Kaoru Shimokata

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Reactive oxidant species are implicated in the chronic airway inflammation related to asthma and chronic obstructive pulmonary disease. This study was designed to determine mechanisms underlying contraction induced by hydrogen peroxide (H2O2), a clinical marker of oxidative stress, in airway smooth muscle. Isometric tension and fluorescent intensities of fura-2, an index of intracellular Ca2+ concentrations ([Ca2+]i), were measured in epithelium-denuded tracheal smooth muscle tissues isolated from guinea pigs. H2O2 (0.01-1 mM) caused contraction with an augmentation of [Ca2+]i in a concentration-dependent manner in the normal physiological solution containing 2.4 mM of extracellular Ca2+ concentrations. The contractile force and [Ca2+]i by H2O2 (1 mM) were approximately half of those in response to 1 μM methacholine. However, contraction by H2O2 was not generated under the condition that extracellular Ca2+ concentrations were less than 0.15 mM. Verapamil (10 μM), an inhibitor of voltage-operated Ca2+ channels, partially but significantly inhibited the H2O2-induced contraction. In contrast, SKF-96365 (1-{β-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl}-1H-imidazole hydrochloride) (100 μM), a non-selective inhibitor of Ca2+ channels, completely abolished both the contraction and the increase in [Ca2+]i elicited by H2O2. Moreover, Y-27632 ((R)-(+)-trans-N-(4-Pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide) (0.03-10 μM), an inhibitor of Rho-kinase, caused a concentration-dependent inhibition of the H2O2-induced contraction. In conclusion, both the Ca2+ influx from the extracellular side and the Ca2+ sensitization by Rho-kinase are involved in the regulation of airway smooth muscle tone induced by H2O2. An inhibition of the Rho/Rho-kinase pathway may be beneficial for the treatment of airflow limitation mediated by oxidative stress.

Original languageEnglish
Pages (from-to)151-156
Number of pages6
JournalEuropean Journal of Pharmacology
Volume556
Issue number1-3
DOIs
Publication statusPublished - 05-02-2007

Fingerprint

rho-Associated Kinases
Hydrogen Peroxide
Smooth Muscle
1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole
Oxidative Stress
Methacholine Chloride
Fura-2
Verapamil
Oxidants
Chronic Obstructive Pulmonary Disease
Guinea Pigs
Asthma
Epithelium
Biomarkers
Inflammation
Muscles
Y 27632

All Science Journal Classification (ASJC) codes

  • Cellular and Molecular Neuroscience
  • Pharmacology

Cite this

Kojima, Katsuyuki ; Kume, Hiroaki ; Ito, Satoru ; Oguma, Tetsuya ; Shiraki, Akira ; Kondo, Masashi ; Ito, Yasushi ; Shimokata, Kaoru. / Direct effects of hydrogen peroxide on airway smooth muscle tone : Roles of Ca2+ influx and Rho-kinase. In: European Journal of Pharmacology. 2007 ; Vol. 556, No. 1-3. pp. 151-156.
@article{8acfd27d320540598bf7dd6239b918cd,
title = "Direct effects of hydrogen peroxide on airway smooth muscle tone: Roles of Ca2+ influx and Rho-kinase",
abstract = "Reactive oxidant species are implicated in the chronic airway inflammation related to asthma and chronic obstructive pulmonary disease. This study was designed to determine mechanisms underlying contraction induced by hydrogen peroxide (H2O2), a clinical marker of oxidative stress, in airway smooth muscle. Isometric tension and fluorescent intensities of fura-2, an index of intracellular Ca2+ concentrations ([Ca2+]i), were measured in epithelium-denuded tracheal smooth muscle tissues isolated from guinea pigs. H2O2 (0.01-1 mM) caused contraction with an augmentation of [Ca2+]i in a concentration-dependent manner in the normal physiological solution containing 2.4 mM of extracellular Ca2+ concentrations. The contractile force and [Ca2+]i by H2O2 (1 mM) were approximately half of those in response to 1 μM methacholine. However, contraction by H2O2 was not generated under the condition that extracellular Ca2+ concentrations were less than 0.15 mM. Verapamil (10 μM), an inhibitor of voltage-operated Ca2+ channels, partially but significantly inhibited the H2O2-induced contraction. In contrast, SKF-96365 (1-{β-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl}-1H-imidazole hydrochloride) (100 μM), a non-selective inhibitor of Ca2+ channels, completely abolished both the contraction and the increase in [Ca2+]i elicited by H2O2. Moreover, Y-27632 ((R)-(+)-trans-N-(4-Pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide) (0.03-10 μM), an inhibitor of Rho-kinase, caused a concentration-dependent inhibition of the H2O2-induced contraction. In conclusion, both the Ca2+ influx from the extracellular side and the Ca2+ sensitization by Rho-kinase are involved in the regulation of airway smooth muscle tone induced by H2O2. An inhibition of the Rho/Rho-kinase pathway may be beneficial for the treatment of airflow limitation mediated by oxidative stress.",
author = "Katsuyuki Kojima and Hiroaki Kume and Satoru Ito and Tetsuya Oguma and Akira Shiraki and Masashi Kondo and Yasushi Ito and Kaoru Shimokata",
year = "2007",
month = "2",
day = "5",
doi = "10.1016/j.ejphar.2006.11.007",
language = "English",
volume = "556",
pages = "151--156",
journal = "European Journal of Pharmacology",
issn = "0014-2999",
publisher = "Elsevier",
number = "1-3",

}

Direct effects of hydrogen peroxide on airway smooth muscle tone : Roles of Ca2+ influx and Rho-kinase. / Kojima, Katsuyuki; Kume, Hiroaki; Ito, Satoru; Oguma, Tetsuya; Shiraki, Akira; Kondo, Masashi; Ito, Yasushi; Shimokata, Kaoru.

In: European Journal of Pharmacology, Vol. 556, No. 1-3, 05.02.2007, p. 151-156.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Direct effects of hydrogen peroxide on airway smooth muscle tone

T2 - Roles of Ca2+ influx and Rho-kinase

AU - Kojima, Katsuyuki

AU - Kume, Hiroaki

AU - Ito, Satoru

AU - Oguma, Tetsuya

AU - Shiraki, Akira

AU - Kondo, Masashi

AU - Ito, Yasushi

AU - Shimokata, Kaoru

PY - 2007/2/5

Y1 - 2007/2/5

N2 - Reactive oxidant species are implicated in the chronic airway inflammation related to asthma and chronic obstructive pulmonary disease. This study was designed to determine mechanisms underlying contraction induced by hydrogen peroxide (H2O2), a clinical marker of oxidative stress, in airway smooth muscle. Isometric tension and fluorescent intensities of fura-2, an index of intracellular Ca2+ concentrations ([Ca2+]i), were measured in epithelium-denuded tracheal smooth muscle tissues isolated from guinea pigs. H2O2 (0.01-1 mM) caused contraction with an augmentation of [Ca2+]i in a concentration-dependent manner in the normal physiological solution containing 2.4 mM of extracellular Ca2+ concentrations. The contractile force and [Ca2+]i by H2O2 (1 mM) were approximately half of those in response to 1 μM methacholine. However, contraction by H2O2 was not generated under the condition that extracellular Ca2+ concentrations were less than 0.15 mM. Verapamil (10 μM), an inhibitor of voltage-operated Ca2+ channels, partially but significantly inhibited the H2O2-induced contraction. In contrast, SKF-96365 (1-{β-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl}-1H-imidazole hydrochloride) (100 μM), a non-selective inhibitor of Ca2+ channels, completely abolished both the contraction and the increase in [Ca2+]i elicited by H2O2. Moreover, Y-27632 ((R)-(+)-trans-N-(4-Pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide) (0.03-10 μM), an inhibitor of Rho-kinase, caused a concentration-dependent inhibition of the H2O2-induced contraction. In conclusion, both the Ca2+ influx from the extracellular side and the Ca2+ sensitization by Rho-kinase are involved in the regulation of airway smooth muscle tone induced by H2O2. An inhibition of the Rho/Rho-kinase pathway may be beneficial for the treatment of airflow limitation mediated by oxidative stress.

AB - Reactive oxidant species are implicated in the chronic airway inflammation related to asthma and chronic obstructive pulmonary disease. This study was designed to determine mechanisms underlying contraction induced by hydrogen peroxide (H2O2), a clinical marker of oxidative stress, in airway smooth muscle. Isometric tension and fluorescent intensities of fura-2, an index of intracellular Ca2+ concentrations ([Ca2+]i), were measured in epithelium-denuded tracheal smooth muscle tissues isolated from guinea pigs. H2O2 (0.01-1 mM) caused contraction with an augmentation of [Ca2+]i in a concentration-dependent manner in the normal physiological solution containing 2.4 mM of extracellular Ca2+ concentrations. The contractile force and [Ca2+]i by H2O2 (1 mM) were approximately half of those in response to 1 μM methacholine. However, contraction by H2O2 was not generated under the condition that extracellular Ca2+ concentrations were less than 0.15 mM. Verapamil (10 μM), an inhibitor of voltage-operated Ca2+ channels, partially but significantly inhibited the H2O2-induced contraction. In contrast, SKF-96365 (1-{β-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl}-1H-imidazole hydrochloride) (100 μM), a non-selective inhibitor of Ca2+ channels, completely abolished both the contraction and the increase in [Ca2+]i elicited by H2O2. Moreover, Y-27632 ((R)-(+)-trans-N-(4-Pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide) (0.03-10 μM), an inhibitor of Rho-kinase, caused a concentration-dependent inhibition of the H2O2-induced contraction. In conclusion, both the Ca2+ influx from the extracellular side and the Ca2+ sensitization by Rho-kinase are involved in the regulation of airway smooth muscle tone induced by H2O2. An inhibition of the Rho/Rho-kinase pathway may be beneficial for the treatment of airflow limitation mediated by oxidative stress.

UR - http://www.scopus.com/inward/record.url?scp=33846110374&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33846110374&partnerID=8YFLogxK

U2 - 10.1016/j.ejphar.2006.11.007

DO - 10.1016/j.ejphar.2006.11.007

M3 - Article

C2 - 17157292

AN - SCOPUS:33846110374

VL - 556

SP - 151

EP - 156

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

SN - 0014-2999

IS - 1-3

ER -