期刊
VASCULAR PHARMACOLOGY
卷 71, 期 -, 页码 181-191出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.vph.2015.03.007
关键词
Nitroglycerin tolerance; sGC activator; sGC stimulator; Oxidative stress; Endothelial dysfunction
资金
- Bayer Pharma AG, Wuppertal, Germany
- Center of Thrombosis and Hemostasis (Mainz, Germany) - Federal Ministry of Education and Research [BMBF 01EO1003]
- Institute of Molecular Biology gGmbH, (Mainz, Germany)
- Boehringer Ingelheim Foundation
Chronic nitroglycerin (GTN) anti-ischemic therapy induces side effects such as nitrate tolerance and endothelial dysfunction. Both phenomena could be based on a desensitization/oxidation of the soluble guanylyl cyclase (sGC). Therefore, the present study aims at investigating the effects of the therapy with the sGC activator BAY 60-2770 and the sGC stimulator BAY 41-8543 on side effects induced by chronic nitroglycerin treatment. Male Wistar rats were treated with nitroglycerin (100 mg/kg/d for 3.5 days, s.c. in ethanol) and BAY 60-2770 (0.5 or 2.5 mg/kg/d) or BAY 41-8543 (1 and 5 mg/kg/d) for 6 days. Therapy with BAY 60-2770 but not with BAY 41-8543 improved nitroglycerin-triggered endothelial dysfunction and nitrate tolerance, corrected the decrease in aortic nitric oxide levels, improved the cGMP dependent activation of protein kinase I in aortic tissue and reduced vascular, cardiac and whole blood oxidative stress (fluorescence and chemiluminescence assays; 3-nitrotyrosine staining). In contrast to BAY 41-8543, the vasodilator potency of BAY 60-2770 was not impaired in isolated aortic ring segments from nitrate tolerant rats. sGC activator therapy improves partially the adverse effects of nitroglycerin therapy whereas sGC stimulation has only minor beneficial effects pointing to a nitroglycerin-dependent sGC oxidation/inactivation mechanism contributing to nitrate tolerance. (C) 2015 Elsevier Inc All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据