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

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.

• Authors: Shogo Tanno, Kenshiro Yamamoto, Yasutaka Kurata, Maya Adachi, Yumiko Inoue, Naoyuki Otani, Mutsuo Mishima, Yasutaka Yamamoto, Masanari Kuwabara, Kazuhide Ogino, Junichiro Miake, Haruaki Ninomiya, Yasuaki Shirayoshi, Futoshi Okada, Kazuhiro Yamamoto, Ichiro Hisatome
• Journal: Circulation journal : official journal of the Japanese Circulation Society (Circ J) Vol. 82 Issue 4 Pg. 1101-1111 (03 23 2018) ISSN: 1347-4820 [Electronic] Japan
• PMID: 29491325 (Publication Type: Journal Article)

Chemical References

• Nitriles
• Protective Agents
• Pyridines
• Reactive Oxygen Species
• Thiobarbituric Acid Reactive Substances
• FYX-051
• Allopurinol
• Xanthine Dehydrogenase

Topics

• Allopurinol (pharmacology, therapeutic use)
• Animals
• Arrhythmias, Cardiac (drug therapy)
• Myocardial Reperfusion Injury (drug therapy)
• Nitriles (pharmacology, therapeutic use)
• Protective Agents (pharmacology, therapeutic use)
• Pyridines (pharmacology, therapeutic use)
• Rats
• Reactive Oxygen Species (metabolism)
• Thiobarbituric Acid Reactive Substances (metabolism)
• Ventricular Dysfunction, Left (prevention & control)
• Xanthine Dehydrogenase (antagonists & inhibitors)