title: Nitrosonifedipine ameliorates angiotensin II-induced vascular remodeling via antioxidative effects.
abstract: Nifedipine is unstable under light and decomposes to a stable nitroso analog, nitrosonifedipine (NO-NIF). The ability of NO-NIF to block calcium channels is quite weak compared with that of nifedipine. Recently, we have demonstrated that NO-NIF reacts with unsaturated fatty acid leading to generate NO-NIF radical, which acquires radical scavenging activity. However, the effects of NO-NIF on the pathogenesis related with oxidative stress, such as atherosclerosis and hypertension, are unclear. In this study, we investigated the effects of NO-NIF on angiotensin II (Ang II)-induced vascular remodeling. Ang II-induced thickening and fibrosis of aorta were inhibited by NO-NIF in mice. NO-NIF decreased reactive oxygen species (ROS) in the aorta and urinary 8-hydroxy-20-deoxyguanosine. Ang II-stimulated mRNA expressions of p22(phox), CD68, F4/80, monocyte chemoattractant protein-1, and collagen I in the aorta were inhibited by NO-NIF. Moreover, NO-NIF inhibited Ang II-induced cell migration and proliferation of vascular smooth muscle cells (VSMCs). NO-NIF reduced Ang II-induced ROS to the control level detected by dihydroethidium staining and lucigenin chemiluminescence assay in VSMCs. NO-NIF suppressed phosphorylations of Akt and epidermal growth factor receptor induced by Ang II. However, NO-NIF had no effects on intracellular Ca(2+) increase and protein kinase C-δ phosphorylation induced by Ang II in VSMCs. The electron paramagnetic resonance spectra indicated the continuous generation of NO-NIF radical of reaction with cultured VSMCs. These findings suggest that NO-NIF improves Ang II-induced vascular remodeling via the attenuation of oxidative stress.
authors.affiliation: Department of Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15, Kuramoto, Tokushima, 770-8503, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Sakurada
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ishizawa
authors.forename: Masaki
authors.initials: M
authors.lastname: Imanishi
authors.forename: Yuki
authors.initials: Y
authors.lastname: Izawa-Ishizawa
authors.forename: Shoko
authors.initials: S
authors.lastname: Fujii
authors.forename: Erika
authors.initials: E
authors.lastname: Tominaga
authors.forename: Teppei
authors.initials: T
authors.lastname: Tsuneishi
authors.forename: Yuya
authors.initials: Y
authors.lastname: Horinouchi
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Kihira
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Shuhei
authors.initials: S
authors.lastname: Tomita
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Aihara
authors.forename: Kazuo
authors.initials: K
authors.lastname: Minakuchi
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tamaki
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005355:Fibrosis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D009603:Nitroso Compounds; D017382:Reactive Oxygen Species; D000804:Angiotensin II; C539379:nitrosonifedipine; D009543:Nifedipine; D002118:Calcium