Nicorandil inhibits angiotensin-II-induced proliferation of cultured rat cardiac fibroblasts

Jer Young Liou, Hong Jye Hong, Li-Chin Sung, Hung Hsing Chao, Po Yuan Chen, Tzu-Hurng Cheng, Paul Chan, Ju Chi Liu

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Background/Aims: Nicorandil, an ATP-sensitive potassium (KATP) channel opener, nitric oxide (NO) donor and antioxidant, was shown to exert a variety of pharmacological effects including cardioprotective properties. However, its mechanisms of action are not completely understood. The aims of this study were to examine whether nicorandil may alter angiotensin-II (Ang II)-induced cell proliferation and to identify the putative underlying signaling pathways in rat cardiac fibroblasts. Methods: Cultured rat cardiac fibroblasts were pretreated with nicorandil, then stimulated with Ang II, and cell proliferation and endothelin-1 (ET-1) expression were examined. The effects of nicorandil on Ang-II-induced reactive oxygen species (ROS) formation and extracellular signal-regulated kinase (ERK) phosphorylation were also examined. In addition, the effects of nicorandil on NO production and endothelial nitric oxide synthase (eNOS) phosphorylation were tested to elucidate the intracellular mechanism. Results: Nicorandil (0.1-10 μmol/l) caused a concentration- dependent inhibition of Ang-II-increased cell proliferation and ET-1 expression which were prevented by the KATP channel blocker glibenclamide (1 μmol/l). Nicorandil also inhibited Ang-II-increased ROS and ERK phosphorylation. In addition, nicorandil was found to increase the NO and eNOS phosphorylation. N-nitro-L-arginine methyl ester, an inhibitor of NOS, and the short interfering RNA transfection for eNOS markedly attenuated the inhibitory effect of nicorandil on Ang-II-induced cell proliferation. Conclusion: Our results suggest that nicorandil prevents cardiac fibroblast proliferation, and the inhibitory effect might be associated with the opening KATP channels, by interfering with the generation of ROS, and the activation of the eNOS-NO pathway.

Original languageEnglish
Pages (from-to)144-151
Number of pages8
JournalPharmacology
Volume87
Issue number3-4
DOIs
Publication statusPublished - Apr 2011

Fingerprint

Nicorandil
Angiotensin II
Fibroblasts
KATP Channels
Nitric Oxide Synthase Type III
Phosphorylation
Cell Proliferation
Reactive Oxygen Species
Nitric Oxide
Extracellular Signal-Regulated MAP Kinases
Endothelin-1
Nitric Oxide Donors
Glyburide
Small Interfering RNA
Transfection
Antioxidants
Pharmacology

Keywords

  • Angiotensin II
  • Cardiac fibroblast proliferation
  • Nicorandil
  • Nitric oxide

ASJC Scopus subject areas

  • Pharmacology

Cite this

Nicorandil inhibits angiotensin-II-induced proliferation of cultured rat cardiac fibroblasts. / Liou, Jer Young; Hong, Hong Jye; Sung, Li-Chin; Chao, Hung Hsing; Chen, Po Yuan; Cheng, Tzu-Hurng; Chan, Paul; Liu, Ju Chi.

In: Pharmacology, Vol. 87, No. 3-4, 04.2011, p. 144-151.

Research output: Contribution to journalArticle

Liou, Jer Young ; Hong, Hong Jye ; Sung, Li-Chin ; Chao, Hung Hsing ; Chen, Po Yuan ; Cheng, Tzu-Hurng ; Chan, Paul ; Liu, Ju Chi. / Nicorandil inhibits angiotensin-II-induced proliferation of cultured rat cardiac fibroblasts. In: Pharmacology. 2011 ; Vol. 87, No. 3-4. pp. 144-151.
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T1 - Nicorandil inhibits angiotensin-II-induced proliferation of cultured rat cardiac fibroblasts

AU - Liou, Jer Young

AU - Hong, Hong Jye

AU - Sung, Li-Chin

AU - Chao, Hung Hsing

AU - Chen, Po Yuan

AU - Cheng, Tzu-Hurng

AU - Chan, Paul

AU - Liu, Ju Chi

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N2 - Background/Aims: Nicorandil, an ATP-sensitive potassium (KATP) channel opener, nitric oxide (NO) donor and antioxidant, was shown to exert a variety of pharmacological effects including cardioprotective properties. However, its mechanisms of action are not completely understood. The aims of this study were to examine whether nicorandil may alter angiotensin-II (Ang II)-induced cell proliferation and to identify the putative underlying signaling pathways in rat cardiac fibroblasts. Methods: Cultured rat cardiac fibroblasts were pretreated with nicorandil, then stimulated with Ang II, and cell proliferation and endothelin-1 (ET-1) expression were examined. The effects of nicorandil on Ang-II-induced reactive oxygen species (ROS) formation and extracellular signal-regulated kinase (ERK) phosphorylation were also examined. In addition, the effects of nicorandil on NO production and endothelial nitric oxide synthase (eNOS) phosphorylation were tested to elucidate the intracellular mechanism. Results: Nicorandil (0.1-10 μmol/l) caused a concentration- dependent inhibition of Ang-II-increased cell proliferation and ET-1 expression which were prevented by the KATP channel blocker glibenclamide (1 μmol/l). Nicorandil also inhibited Ang-II-increased ROS and ERK phosphorylation. In addition, nicorandil was found to increase the NO and eNOS phosphorylation. N-nitro-L-arginine methyl ester, an inhibitor of NOS, and the short interfering RNA transfection for eNOS markedly attenuated the inhibitory effect of nicorandil on Ang-II-induced cell proliferation. Conclusion: Our results suggest that nicorandil prevents cardiac fibroblast proliferation, and the inhibitory effect might be associated with the opening KATP channels, by interfering with the generation of ROS, and the activation of the eNOS-NO pathway.

AB - Background/Aims: Nicorandil, an ATP-sensitive potassium (KATP) channel opener, nitric oxide (NO) donor and antioxidant, was shown to exert a variety of pharmacological effects including cardioprotective properties. However, its mechanisms of action are not completely understood. The aims of this study were to examine whether nicorandil may alter angiotensin-II (Ang II)-induced cell proliferation and to identify the putative underlying signaling pathways in rat cardiac fibroblasts. Methods: Cultured rat cardiac fibroblasts were pretreated with nicorandil, then stimulated with Ang II, and cell proliferation and endothelin-1 (ET-1) expression were examined. The effects of nicorandil on Ang-II-induced reactive oxygen species (ROS) formation and extracellular signal-regulated kinase (ERK) phosphorylation were also examined. In addition, the effects of nicorandil on NO production and endothelial nitric oxide synthase (eNOS) phosphorylation were tested to elucidate the intracellular mechanism. Results: Nicorandil (0.1-10 μmol/l) caused a concentration- dependent inhibition of Ang-II-increased cell proliferation and ET-1 expression which were prevented by the KATP channel blocker glibenclamide (1 μmol/l). Nicorandil also inhibited Ang-II-increased ROS and ERK phosphorylation. In addition, nicorandil was found to increase the NO and eNOS phosphorylation. N-nitro-L-arginine methyl ester, an inhibitor of NOS, and the short interfering RNA transfection for eNOS markedly attenuated the inhibitory effect of nicorandil on Ang-II-induced cell proliferation. Conclusion: Our results suggest that nicorandil prevents cardiac fibroblast proliferation, and the inhibitory effect might be associated with the opening KATP channels, by interfering with the generation of ROS, and the activation of the eNOS-NO pathway.

KW - Angiotensin II

KW - Cardiac fibroblast proliferation

KW - Nicorandil

KW - Nitric oxide

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