title: Cardioprotective effect of TY-12533, a novel Na(+)/H(+) exchange inhibitor, on ischemia/reperfusion injury.
abstract: The effects of 6,7,8, 9-tetrahydro-2-methyl-5H-cyclohepta[b]pyridine-3-carbonylguanidine maleate (TY-12533) on myocardial ischemia/reperfusion injury were evaluated in rats. Inhibitory effects of TY-12533, TY-50893 (the 9-chloro derivative of TY-12533) and cariporide on the platelet Na(+)/H(+) exchanger in vitro were almost equal at pH 6.2 and decreased at pH 6.7; but TY-12533 was four times more potent than TY-50893 and cariporide at pH 6.7. TY-12533, TY-50893 and cariporide administered before ischemia (0.01-1 mg/kg, i.v.) suppressed the ischemia/reperfusion-induced arrhythmias to the same extent in vivo; but TY-12533 was more effective than cariporide and TY-50893 when they were administered during ischemia (0.1-1 mg/kg). Similar results were obtained for the inhibitory effects of these drugs administered before ischemia (0.03-0.1 mg/kg, i.v.) and during ischemia (0.1-1 mg/kg) on the ischemia/reperfusion-induced myocardial infarction. These differences between TY-12533 and the other drugs in vitro and in vivo may be ascribed to the pK(a) values of the guanidinium moiety of TY-12533 (6.93), TY-50893 (6.35) and cariporide (6.28).
authors.affiliation: Laboratory of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, 980-8578, Sendai, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Aihara
authors.forename: H
authors.initials: H
authors.lastname: Hisa
authors.forename: T
authors.initials: T
authors.lastname: Sato
authors.forename: F
authors.initials: F
authors.lastname: Yoneyama
authors.forename: J
authors.initials: J
authors.lastname: Sasamori
authors.forename: F
authors.initials: F
authors.lastname: Yamaguchi
authors.forename: S
authors.initials: S
authors.lastname: Yoneyama
authors.forename: Y
authors.initials: Y
authors.lastname: Mizuno
authors.forename: A
authors.initials: A
authors.lastname: Takahashi
authors.forename: A
authors.initials: A
authors.lastname: Nagai
authors.forename: T
authors.initials: T
authors.lastname: Kimura
authors.forename: K
authors.initials: K
authors.lastname: Kogi
authors.forename: S
authors.initials: S
authors.lastname: Satoh
mesh_terms: D000157:Aconitine; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000209:etiology; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D006146:Guanidines / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000209:etiology; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000889:Anti-Arrhythmia Agents; D002316:Cardiotonic Agents; D006146:Guanidines; D011725:Pyridines; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C420123:TY 12533; C093373:cariporide; D000157:Aconitine