title: Endothelium-derived hydrogen peroxide accounts for the enhancing effect of an angiotensin-converting enzyme inhibitor on endothelium-derived hyperpolarizing factor-mediated responses in mice.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Fujiki
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
authors.forename: Keiko
authors.initials: K
authors.lastname: Morikawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kubota
authors.forename: Makoto
authors.initials: M
authors.lastname: Hatanaka
authors.forename: M A Hassan
authors.initials: MA
authors.lastname: Talukder
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Matoba
authors.forename: Akira
authors.initials: A
authors.lastname: Takeshita
authors.forename: Kenji
authors.initials: K
authors.lastname: Sunagawa
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D001685:Biological Factors / Q000378:metabolism*; D001794:Blood Pressure; D001835:Body Weight; D002374:Catalase / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism*; D004958:Estradiol / Q000097:blood; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism*; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D013482:Superoxide Dismutase / Q000378:metabolism; D013841:Thiazepines / Q000097:blood / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D001685:Biological Factors; D013841:Thiazepines; C067410:endothelium-dependent hyperpolarization factor; C069156:temocaprilat; D004958:Estradiol; C055603:temocapril hydrochloride; D006861:Hydrogen Peroxide; D002374:Catalase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D013482:Superoxide Dismutase; D005978:Glutathione