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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:766.)
© 2005 American Heart Association, Inc.

Vascular Biology

Endothelium-Derived Hydrogen Peroxide Accounts for the Enhancing Effect of an Angiotensin-Converting Enzyme Inhibitor on Endothelium-Derived Hyperpolarizing Factor–Mediated Responses in Mice

Takako Fujiki; Hiroaki Shimokawa; Keiko Morikawa; Hiroshi Kubota; Makoto Hatanaka; M.A. Hassan Talukder; Tetsuya Matoba; Akira Takeshita; Kenji Sunagawa

From the Department of Cardiovascular Medicine (T.F., H.S., K.M., H.K., M.H., M.A.T., T.M., A.T., K.S.), Kyushu University Graduate School of Medical Sciences, and the Kyushu University COE Program on Lifestyle-related Diseases (H.S.), Fukuoka, Japan.

Correspondence to Hiroaki Shimokawa, MD, PhD, Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail shimo{at}cardiol.med.kyushu-u.ac.jp

Background— We have recently identified that endothelium-derived hydrogen peroxide (H₂O₂) is an endothelium-derived hyperpolarizing factor (EDHF) in animals and humans, for which endothelial nitric oxide synthase (eNOS) is an important source. Angiotensin-converting enzyme (ACE) inhibitors are known to enhance EDHF-mediated responses. In this study, we examined whether endothelium-derived H₂O₂ accounts for the enhancing effect of an ACE inhibitor on EDHF-mediated responses and, if so, what mechanism is involved.

Methods and Results— Control and eNOS^–/– mice were maintained with or without temocapril (10 mg/kg per day orally) for 4 weeks, and isometric tensions and membrane potentials of mesenteric arteries were recorded. In control mice, temocapril treatment significantly enhanced EDHF-mediated relaxations and hyperpolarizations to acetylcholine (n=8 each). Catalase, a specific scavenger of H₂O₂, abolished the beneficial effects of temocapril, although it did not affect endothelium-independent relaxations to sodium nitroprusside or NS1619, a direct opener of K_Ca channels (n=6 each). Western blot analysis demonstrated that the temocapril treatment significantly upregulated the expression of eNOS. By contrast, this enhancing effect of temocapril was absent in eNOS^–/– mice (n=6).

Conclusions— These results indicate that endothelium-derived H₂O₂ accounts for the enhancing effect of temocapril on EDHF-mediated responses caused in part by eNOS upregulation, further supporting our H₂O₂ theory.

This study was designed to examine the involvement of H₂O₂/EDHF in the effect of an ACE inhibitor in mice. The results showed that endothelium-derived H₂O₂ is involved in the enhancing effect of temocapril on EDHF-mediated responses in control but not in eNOS^–/– mice, thus further supporting our H₂O₂ theory.

Key Words: angiotensin-converting enzyme inhibitors • endothelium-derived factors • nitric oxide synthase • vasodilation

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