Cardioprotective effect of TY-12533, a novel Na(+)/H(+) exchange inhibitor, on ischemia/reperfusion injury.
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).
Aihara
K
K
Laboratory of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, 980-8578, Sendai, Japan.
Hisa
H
H
Sato
T
T
Yoneyama
F
F
Sasamori
J
J
Yamaguchi
F
F
Yoneyama
S
S
Mizuno
Y
Y
Takahashi
A
A
Nagai
A
A
Kimura
T
T
Kogi
K
K
Satoh
S
S
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
D000889:Anti-Arrhythmia Agents; D002316:Cardiotonic Agents; D006146:Guanidines; D011725:Pyridines; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C420123:TY 12533; C093373:cariporide; D000157:Aconitine