title: The cardioprotective effects of novel Na+/H+ exchanger inhibitor TY-51924 on ischemia/reperfusion injury.
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 NH(4)Cl 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.
authors: *Department of R&D, Fukushima Research Laboratories, TOA EIYO LTD, Fukushima, Japan; and †Department of R&D, Tokyo Research Laboratories, TOA EIYO LTD, Saitama, Japan.
authors: Jun
authors: J
authors: Sasamori
authors: Takeshi
authors: T
authors: Hasegawa
authors: Akiyuki
authors: A
authors: Takaya
authors: Yoshiaki
authors: Y
authors: Watanabe
authors: Marie
authors: M
authors: Tanaka
authors: Yamato
authors: Y
authors: Ogino
authors: Toshiki
authors: T
authors: Chiba
authors: Kazuyuki
authors: K
authors: Aihara
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D003326:Coronary Circulation / Q000187:drug effects; D003402:Creatine Kinase / Q000097:blood; D004285:Dogs; D006146:Guanidines / Q000627:therapeutic use*; D006439:Hemodynamics / Q000187:drug effects; D007536:Isomerism; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013463:Sulfuric Acid Esters / Q000627:therapeutic use*
chemical_list: C000592017:3-guanidinocarbonyl-2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta(b)pyridine-9-ylmethyl sulfuric acid; D002316:Cardiotonic Agents; D006146:Guanidines; D017923:Sodium-Hydrogen Exchangers; D013463:Sulfuric Acid Esters; D003402:Creatine Kinase