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Journal of Cardiovascular Pharmacology:
doi: 10.1097/FJC.0000000000000055
Original Article

The Cardioprotective Effects of Novel Na+/H+ Exchanger Inhibitor TY-51924 on Ischemia/Reperfusion Injury

Sasamori, Jun MSc*; Hasegawa, Takeshi MSc*; Takaya, Akiyuki PhD; Watanabe, Yoshiaki MSc*; Tanaka, Marie MSc*; Ogino, Yamato MSc*; Chiba, Toshiki MSc*; Aihara, Kazuyuki PhD*

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Abstract

Abstract: The inhibitory effects of sodium 3-guanidinocarbonyl-2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-9-ylmethyl sulfate monoethanolate (TY-51924) are selective for Na+/H+ exchanger (NHE)-1 in PS120 cells expressing human NHE isoforms assayed by NH4Cl prepulse technique. The median inhibitory concentrations (micromolar) of TY-51924 were 0.095 ± 0.008 (NHE-1), 0.621 ± 0.093 (NHE-2), and >100 (NHE-3). In anesthetized dogs subjected to 90 minutes ischemia/300 minutes reperfusion, intravenous bolus TY-51924 at 5 and 10 mg/kg administered 5 minutes before reperfusion reduced infarct size. The infarct size reduction ratios of TY-51924 at 5 and 10 mg/kg versus vehicle were 32.8% and 52.4%, respectively. But TY-51924 at 10 mg/kg administered 10 minutes after reperfusion did not reduce infarct size. In 2-step intravenous infusion initiated 15 minutes before reperfusion, TY-51924 at low dose (3.8 mg/kg per 5 minutes, then 6.2 mg/kg per 20 minutes) and at high dose (7.6 mg/kg per 5 minutes, then 12.4 mg/kg per 20 minutes) reduced infarct size. The infarct size reduction ratios of TY-51924 at 10 and 20 mg/kg versus vehicle were 39.2% and 51.7%, respectively; plasma drug concentrations at reperfusion were 16.8 and 38.8 μg/mL, respectively. This indicates that maintaining a plasma drug concentration of >20 μg/mL at reperfusion enables TY-51924 to reduce infarct size by inhibiting the NHE, which is activated during the early period of reperfusion.

© 2014 by Lippincott Williams & Wilkins.

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