title: Possible usefulness of apocynin, an NADPH oxidase inhibitor, for nitrate tolerance: prevention of NO donor-induced endothelial cell abnormalities.
abstract: The long-term benefits of nitroglycerin therapy are limited by tolerance development. Understanding the precise nature of mechanisms underlying nitroglycerin-induced endothelial cell dysfunction may provide new strategies to prevent tolerance development. In this line, we tested interventions to prevent endothelial dysfunction in the setting of nitrate tolerance. When bovine aortic endothelial cells (BAECs) were continuously treated with nitric oxide (NO) donors, including nitroglycerin, over 2-3 days, basal production of nitrite and nitrate (NO(x)) was diminished. The diminished basal NO(x) levels were mitigated by intermittent treatment allowing an 8-h daily nitrate-free interval during the 2- to 3-day treatment period. Addition of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin restored the basal levels of NO(x) that were decreased by continuous nitroglycerin treatment of BAECs. Apocynin caused significant improvement of increased mRNA and protein levels of endothelial nitric oxide synthase (eNOS) in BAECs given nitroglycerin continuously over the treatment period. Apocynin also reduced endothelial production of reactive oxygen species (ROS) after continuous nitroglycerin treatment. These results showed an essential similarity to the effects of a nitrate-free interval. Application of the NOS inhibitor N(omega)-nitro- l-arginine methyl ester caused a recovery effect on basal NO(x) and eNOS expression but was without effect on ROS levels in continuously NO donor-treated BAECs. In conclusion, the present study characterized abnormal features and functions of endothelial cells following continuous NO donor application. We suggest that inhibition of NADPH oxidase, by preventing NO donor-induced endothelial dysfunction, may represent a potential therapeutic strategy that confers protection from nitrate tolerance development.
authors: Department of Geriatrics, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan.
authors: Akiko
authors: A
authors: Fukatsu
authors: Toshio
authors: T
authors: Hayashi
authors: Asaka
authors: A
authors: Miyazaki-Akita
authors: Hisako
authors: H
authors: Matsui-Hirai
authors: Yukie
authors: Y
authors: Furutate
authors: Asako
authors: A
authors: Ishitsuka
authors: Yuichi
authors: Y
authors: Hattori
authors: Akihisa
authors: A
authors: Iguchi
mesh_terms: D000098:Acetophenones / Q000008:administration & dosage*; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004361:Drug Tolerance / Q000502:physiology; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors*; D009566:Nitrates / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000008:administration & dosage*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000098:Acetophenones; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D009566:Nitrates; D020030:Nitric Oxide Donors; D017382:Reactive Oxygen Species; C056165:acetovanillone; D019255:NADPH Oxidases