title: Voltage-dependent N-type Ca2+ channels in endothelial cells contribute to oxidative stress-related endothelial dysfunction induced by angiotensin II in mice.
abstract: N-type voltage-dependent Ca(2+)channels (VDCCs), expressed predominantly in the nervous system, play pivotal roles in sympathetic regulation of the circulatory system. Although N-type VDCCs are also reportedly expressed in the vasculature, their pathophysiological role is obscure. We demonstrated that oxidative stress-related endothelial dysfunction induced by angiotensin (Ang) II is suppressed in mice lacking the N-type VDCC α1B subunit (Cav 2.2). Impairment of endothelium-dependent relaxation of the thoracic aorta observed following Ang II treatment in wild-type (WT) mice was significantly attenuated in the Ang II-treated Cav 2.2-deficient mice, despite the comparable increase of the blood pressure in the two groups of mice. The thoracic aorta of the Cav 2.2-deficient mice showed a smaller positive area of oxidative stress markers as compared to the WT mice. The Ang II-induced endothelial dysfunction was also suppressed by cilnidipine, an L/N-type VDCC blocker, but not by amlodipine, an L-type VDCC blocker; however, this unique effect of cilnidipine was completely abolished in the Cav 2.2-deficient mice. Furthermore, selective inhibition of N-type VDCCs by ω-conotoxin GVIA dramatically suppressed the production of reactive oxygen species (ROS) as well as agonist-induced Ca(2+) influx in the vascular endothelial cells. These results suggest that N-type VDCCs expressed in the vascular endothelial cells contribute to ROS production and endothelial dysfunction observed in Ang II-treated hypertensive mice.
authors.affiliation: Department of Drug Discovery and Evolution, Graduate School of Pharmaceutical Sciences, Kyushu University, Maidashi 3-1-1, Fukuoka 812-8582, Japan. nishida@phar.kyushu-u.ac.jp
authors.forename: Motohiro
authors.initials: M
authors.lastname: Nishida
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Shota
authors.initials: S
authors.lastname: Saiki
authors.forename: Caroline
authors.initials: C
authors.lastname: Sunggip
authors.forename: Shizuka
authors.initials: S
authors.lastname: Aritomi
authors.forename: Eri
authors.initials: E
authors.lastname: Harada
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kuwahara
authors.forename: Katsuya
authors.initials: K
authors.lastname: Hirano
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Mori
authors.forename: Shokei
authors.initials: S
authors.lastname: Kim-Mitsuyama
mesh_terms: D017311:Amlodipine / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D015415:Biomarkers / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020864:Calcium Channels, N-Type / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D004095:Dihydropyridines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006439:Hemodynamics; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology; D020866:omega-Conotoxin GVIA / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D004095:Dihydropyridines; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D000804:Angiotensin II; D017311:Amlodipine; D020866:omega-Conotoxin GVIA; C065927:cilnidipine; D002118:Calcium