title: Paclitaxel-induced endothelial dysfunction in living rats is prevented by nicorandil via reduction of oxidative stress.
abstract: 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 (p47(phox), gp91(phox) 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 K(ATP) channel activation.
authors: Product Research Department, Chugai Pharmaceutical Co., Ltd., Japan.
authors: Ken-Ichi
authors: K
authors: Serizawa
authors: Kenji
authors: K
authors: Yogo
authors: Ken
authors: K
authors: Aizawa
authors: Yoshihito
authors: Y
authors: Tashiro
authors: Yoko
authors: Y
authors: Takahari
authors: Kaori
authors: K
authors: Sekine
authors: Toshihiko
authors: T
authors: Suzuki
authors: Nobuhiko
authors: N
authors: Ishizuka
authors: Hideyuki
authors: H
authors: Ishida
mesh_terms: D000109:Acetylcholine; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001158:Arteries / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D001783:Blood Flow Velocity / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D005263:Femoral Artery / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D019255:NADPH Oxidases / Q000235:genetics; D020108:Nicorandil / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017239:Paclitaxel / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013737:Testis / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000889:Anti-Arrhythmia Agents; D000972:Antineoplastic Agents, Phytogenic; D017382:Reactive Oxygen Species; D020108:Nicorandil; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases; D000109:Acetylcholine; D017239:Paclitaxel