Paclitaxel-Induced Endothelial Dysfunction in Living Rats Is Prevented by Nicorandil via Reduction of Oxidative Stress

Paclitaxel-eluting stents dramatically reduce rates of in-stent restenosis; however, paclitaxel is known to lead to endothelial dysfunction. Protective effects of nicorandil on paclitaxel-induced endothelial dysfunction by examining flow-mediated dilation (FMD) were investigated in anesthetized rats...

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Main Authors: Ken-ichi Serizawa, Kenji Yogo, Ken Aizawa, Yoshihito Tashiro, Yoko Takahari, Kaori Sekine, Toshihiko Suzuki, Nobuhiko Ishizuka, Hideyuki Ishida
Format: Article
Language:English
Published: Elsevier 2012-01-01
Series:Journal of Pharmacological Sciences
Online Access:http://www.sciencedirect.com/science/article/pii/S1347861319304797
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spelling doaj-79dc6818431c4382858a22754ffa66be2020-11-25T02:30:55ZengElsevierJournal of Pharmacological Sciences1347-86132012-01-011194349358Paclitaxel-Induced Endothelial Dysfunction in Living Rats Is Prevented by Nicorandil via Reduction of Oxidative StressKen-ichi Serizawa0Kenji Yogo1Ken Aizawa2Yoshihito Tashiro3Yoko Takahari4Kaori Sekine5Toshihiko Suzuki6Nobuhiko Ishizuka7Hideyuki Ishida8Product Research Department, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, JapanProduct Research Department, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, JapanProduct Research Department, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, JapanProduct Research Department, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, JapanTeaching and Research Support Center, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, JapanDepartment of Pediatrics, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, JapanDepartment of Physiology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, JapanProduct Research Department, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan; Corresponding author. ishizukanbh@chugai-pharm.co.jp on July 24, 2012 (in advance)Department of Physiology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, JapanPaclitaxel-eluting stents dramatically reduce rates of in-stent restenosis; however, paclitaxel is known to lead to endothelial dysfunction. Protective effects of nicorandil on paclitaxel-induced endothelial dysfunction by examining flow-mediated dilation (FMD) were investigated in anesthetized rats. After 7-day osmotic infusion of paclitaxel (5 mg/kg per day), FMD was measured by high-resolution ultrasound in the femoral artery of living rats. Paclitaxel significantly reduced FMD (21.6% ± 3.2% to 7.1% ± 1.7%); this reduction was prevented by co-treatment with nicorandil (15 mg/kg per day), while paclitaxel did not affect nitroglycerin-induced vasodilation. Diazoxide and tempol, but not isosorbide dinitrate, had an effect similar to nicorandil in preventing paclitaxel-induced decrease in FMD. Nicorandil significantly prevented paclitaxel-induced reduction in acetylcholine-induced vasodilation. On the underling mechanisms, paclitaxel increased reactive oxygen species (ROS) production (dihydrorhodamine 123, DCF fluorescence intensity) and NADPH oxidase (p47phox, gp91phox mRNA) in arteries and human coronary artery endothelial cells (HCAECs), while paclitaxel reduced nitric oxide (NO) release (DAF-2 fluorescence intensity), but not endothelial NO synthase (eNOS) phosphorylation in HCAECs. Nicorandil prevented the increased ROS production in arteries and HCAECs, which was 5-hydroxydecanoate (5-HD)-sensitive but 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ)-resistant, without significant effect on the reduced NO release. In conclusion, nicorandil prevents paclitaxel-induced endothelial dysfunction, which may be brought by improved NO bioavailability due to the reduction of oxidative stress via KATP channel activation. Keywords:: endothelial dysfunction, flow-mediated dilation, nicorandil, paclitaxel, reactive oxygen specieshttp://www.sciencedirect.com/science/article/pii/S1347861319304797
collection DOAJ
language English
format Article
sources DOAJ
author Ken-ichi Serizawa
Kenji Yogo
Ken Aizawa
Yoshihito Tashiro
Yoko Takahari
Kaori Sekine
Toshihiko Suzuki
Nobuhiko Ishizuka
Hideyuki Ishida
spellingShingle Ken-ichi Serizawa
Kenji Yogo
Ken Aizawa
Yoshihito Tashiro
Yoko Takahari
Kaori Sekine
Toshihiko Suzuki
Nobuhiko Ishizuka
Hideyuki Ishida
Paclitaxel-Induced Endothelial Dysfunction in Living Rats Is Prevented by Nicorandil via Reduction of Oxidative Stress
Journal of Pharmacological Sciences
author_facet Ken-ichi Serizawa
Kenji Yogo
Ken Aizawa
Yoshihito Tashiro
Yoko Takahari
Kaori Sekine
Toshihiko Suzuki
Nobuhiko Ishizuka
Hideyuki Ishida
author_sort Ken-ichi Serizawa
title Paclitaxel-Induced Endothelial Dysfunction in Living Rats Is Prevented by Nicorandil via Reduction of Oxidative Stress
title_short Paclitaxel-Induced Endothelial Dysfunction in Living Rats Is Prevented by Nicorandil via Reduction of Oxidative Stress
title_full Paclitaxel-Induced Endothelial Dysfunction in Living Rats Is Prevented by Nicorandil via Reduction of Oxidative Stress
title_fullStr Paclitaxel-Induced Endothelial Dysfunction in Living Rats Is Prevented by Nicorandil via Reduction of Oxidative Stress
title_full_unstemmed Paclitaxel-Induced Endothelial Dysfunction in Living Rats Is Prevented by Nicorandil via Reduction of Oxidative Stress
title_sort paclitaxel-induced endothelial dysfunction in living rats is prevented by nicorandil via reduction of oxidative stress
publisher Elsevier
series Journal of Pharmacological Sciences
issn 1347-8613
publishDate 2012-01-01
description Paclitaxel-eluting stents dramatically reduce rates of in-stent restenosis; however, paclitaxel is known to lead to endothelial dysfunction. Protective effects of nicorandil on paclitaxel-induced endothelial dysfunction by examining flow-mediated dilation (FMD) were investigated in anesthetized rats. After 7-day osmotic infusion of paclitaxel (5 mg/kg per day), FMD was measured by high-resolution ultrasound in the femoral artery of living rats. Paclitaxel significantly reduced FMD (21.6% ± 3.2% to 7.1% ± 1.7%); this reduction was prevented by co-treatment with nicorandil (15 mg/kg per day), while paclitaxel did not affect nitroglycerin-induced vasodilation. Diazoxide and tempol, but not isosorbide dinitrate, had an effect similar to nicorandil in preventing paclitaxel-induced decrease in FMD. Nicorandil significantly prevented paclitaxel-induced reduction in acetylcholine-induced vasodilation. On the underling mechanisms, paclitaxel increased reactive oxygen species (ROS) production (dihydrorhodamine 123, DCF fluorescence intensity) and NADPH oxidase (p47phox, gp91phox mRNA) in arteries and human coronary artery endothelial cells (HCAECs), while paclitaxel reduced nitric oxide (NO) release (DAF-2 fluorescence intensity), but not endothelial NO synthase (eNOS) phosphorylation in HCAECs. Nicorandil prevented the increased ROS production in arteries and HCAECs, which was 5-hydroxydecanoate (5-HD)-sensitive but 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ)-resistant, without significant effect on the reduced NO release. In conclusion, nicorandil prevents paclitaxel-induced endothelial dysfunction, which may be brought by improved NO bioavailability due to the reduction of oxidative stress via KATP channel activation. Keywords:: endothelial dysfunction, flow-mediated dilation, nicorandil, paclitaxel, reactive oxygen species
url http://www.sciencedirect.com/science/article/pii/S1347861319304797
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