title: Breathing nitric oxide plus hydrogen gas reduces ischemia-reperfusion injury and nitrotyrosine production in murine heart.
abstract: Inhaled nitric oxide (NO) has been reported to decrease the infarct size in cardiac ischemia-reperfusion (I/R) injury. However, reactive nitrogen species (RNS) produced by NO cause myocardial dysfunction and injury. Because H₂ is reported to eliminate peroxynitrite, it was expected to reduce the adverse effects of NO. In mice, left anterior descending coronary artery ligation for 60 min followed by reperfusion was performed with inhaled NO [80 parts per million (ppm)], H₂ (2%), or NO + H₂, starting 5 min before reperfusion for 35 min. After 24 h, left ventricular function, infarct size, and area at risk (AAR) were assessed. Oxidative stress associated with reactive oxygen species (ROS) was evaluated by staining for 8-hydroxy-2'-deoxyguanosine and 4-hydroxy-2-nonenal, that associated with RNS by staining for nitrotyrosine, and neutrophil infiltration by staining for granulocyte receptor-1. The infarct size/AAR decreased with breathing NO or H₂ alone. NO inhalation plus H₂ reduced the infarct size/AAR, with significant interaction between the two, reducing ROS and neutrophil infiltration, and improved the cardiac function to normal levels. Although nitrotyrosine staining was prominent after NO inhalation alone, it was eliminated after breathing a mixture of H₂ with NO. Preconditioning with NO significantly reduced the infarct size/AAR, but not preconditioning with H₂. In conclusion, breathing NO + H₂ during I/R reduced the infarct size and maintained cardiac function, and reduced the generation of myocardial nitrotyrosine associated with NO inhalation. Administration of NO + H₂ gases for inhalation may be useful for planned coronary interventions or for the treatment of I/R injury.
authors.affiliation: Department of Medical Engineering and Technology, Kitasato University School of Allied Health Sciences;
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Shinbo
authors.forename: Kenichi
authors.initials: K
authors.lastname: Kokubo
authors.forename: Yuri
authors.initials: Y
authors.lastname: Sato
authors.forename: Shintaro
authors.initials: S
authors.lastname: Hagiri
authors.forename: Ryuji
authors.initials: R
authors.lastname: Hataishi
authors.forename: Minoru
authors.initials: M
authors.lastname: Hirose
authors.forename: Hirosuke
authors.initials: H
authors.lastname: Kobayashi
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000280:Administration, Inhalation; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage*; D002316:Cardiotonic Agents / Q000008:administration & dosage* / Q000633:toxicity; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005740:Gases; D006859:Hydrogen / Q000008:administration & dosage*; D007150:Immunohistochemistry; D001239:Inhalation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D020556:Neutrophil Infiltration / Q000187:drug effects; D009569:Nitric Oxide / Q000008:administration & dosage* / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000378:metabolism; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D000447:Aldehydes; D000975:Antioxidants; D002316:Cardiotonic Agents; D005740:Gases; D011956:Receptors, Cell Surface; C551746:granulocyte receptor 1, mouse; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D006859:Hydrogen; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine; C027576:4-hydroxy-2-nonenal
keywords: antioxidants; hydrogen gas; ischemia; nitric oxide; reperfusion injury