Protective Effects of Topiroxostat on an Ischemia-Reperfusion Model of Rat Hearts

• Tanno Shogo

  Division of Regenerative Medicine and Therapeutics, Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science

• Yamamoto Kenshiro

  Division of Regenerative Medicine and Therapeutics, Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science

• Kurata Yasutaka

  Department of Physiology, Kanazawa Medical University

• Adachi Maya

  Division of Regenerative Medicine and Therapeutics, Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science

• Inoue Yumiko

  Division of Regenerative Medicine and Therapeutics, Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science

• Otani Naoyuki

  Department of Clinical Pharmacology and Therapeutics, Oita University Faculty of Medicine

• Mishima Mutsuo

  Division of Regenerative Medicine and Therapeutics, Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science

• Yamamoto Yasutaka

  Division of Regenerative Medicine and Therapeutics, Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science

• Kuwabara Masanari

  University of Colorado, Denver, School of Medicine, Division of Renal Diseases and Hypertension

• Ogino Kazuhide

  Department of Clinical Laboratory, Tottori University Hospital

• Miake Junichiro

  Division of Cardiovascular Medicine, Department of Molecular Medicine and Therapeutics, Faculty of Medicine, Tottori University

• Ninomiya Haruaki

  Department of Biological Regulation, Tottori University

• Shirayoshi Yasuaki

  Division of Regenerative Medicine and Therapeutics, Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science

• Okada Futoshi

  Division of Pathological Biochemistry, Faculty of Medicine, Tottori University

• Yamamoto Kazuhiro

  Division of Cardiovascular Medicine, Department of Molecular Medicine and Therapeutics, Faculty of Medicine, Tottori University

• Hisatome Ichiro

  Division of Regenerative Medicine and Therapeutics, Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science

Abstract

Background:Ischemia/reperfusion (I/R) injury triggers cardiac dysfunctions via creating reactive oxygen species (ROS). Because xanthine oxidase (XO) is one of the major enzymes that generate ROS, inhibition of XO is expected to suppress ROS-induced I/R injury. However, it remains unclear whether XO inhibition really yields cardioprotection during I/R. The protective effects of the XO inhibitors, topiroxostat and allopurinol, on cardiac I/R injury were evaluated. Methods and Results:Using isolated rat hearts, ventricular functions, occurrence of arrhythmias, XO activities and thiobarbituric acid reactive substances (TBARS) productions and myocardial levels of adenine nucleotides before and after I/R, and cardiomyocyte death markers during reperfusion, were evaluated. Topiroxostat prevented left ventricular dysfunctions and facilitated recovery from arrhythmias during I/R. Allopurinol and the antioxidant, N-acetylcysteine (NAC), exhibited similar effects at higher concentrations. Topiroxostat inhibited myocardial XO activities and TBARS productions after I/R. I/R decreased myocardial levels of ATP, ADP and AMP, but increased that of xanthine. While topiroxostat, allopurinol or NAC did not change myocardial levels of ATP, ADP or AMP after I/R, all of the agents decreased the level of xanthine. They also decreased releases of CPK and LDH during reperfusion. Conclusions:Topiroxostat showed protective effects against I/R injury with higher potency than allopurinol or NAC. It dramatically inhibited XO activity and TBARS production, suggesting suppression of ROS generation.

Journal

• Circulation Journal

  Circulation Journal 82 (4), 1101-1111, 2018

  The Japanese Circulation Society

Keywords

• Ischemia-reperfusion injury
• Rat heart
• Reactive oxygen species (ROS)
• Topiroxostat
• Xanthine oxidase

Details

• CRID: 1390282680083226112
• NII Article ID: 130006528600
• NII Book ID: AA11591968
• DOI: 10.1253/circj.cj-17-1049
• ISSN: 13474820
• ISSN: 13469843
• NDL BIB ID: 028895530
• PubMed: 29491325
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I028895530
• Web Site: https://www.jstage.jst.go.jp/article/circj/82/4/82_CJ-17-1049/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2018289432
• Text Lang: en
• Data Source:
  • JaLC
  • NDL
  • Crossref
  • PubMed
  • CiNii Articles
  • KAKEN
• Abstract License Flag: Disallowed