Effects of [5-(2-methoxy-5-fluorophenyl)furan-2-ylcarbonyl]guanidine (KR-32560), a novel sodium/hydrogen exchanger-1 inhibitor, on myocardial infarct size and ventricular arrhythmias in a rat model of ischemia/reperfusion heart injury.
The cardioprotective effects of the novel sodium/hydrogen exchanger-1 (NHE-1) inhibitor KR-32560 {[5-(2-methoxy-5-fluorophenyl)furan-2-ylcarbonyl]guanidine} were studied in an anesthetized rat model of 30-min ischemia / 2.5-h reperfusion heart injury. KR-32560 (0.01 - 1 microM) dose-dependently inhibited NHE-1-mediated rabbit platelet swelling induced by intracellular acidification. KR-32560 at 0.1 and 1.0 mg/kg (i.v. bolus, given 10 min before ischemia) reduced infarct size from 65.9% (control) to 49.7% and 32.7%, respectively, while reducing the extension of myocardial injury (mm(3)/g of left heart weight) from 405.1 (control) to 302.9 and 185.4, respectively (all P<0.05 vs control). KR-32560 dose-dependently reduced the total number of ventricular premature beats (VPBs) during ischemia from 510.2 (control) to 353.8 and 134.2 beats (all P<0.05, n = 6), while reducing ventricular tachycardia (VT) incidence from 49.3 (control) to 26.8 and 4.3 and VT duration from 249.2 s (control) to 150.5 and 26.7 s (all P<0.05, n = 6). KR-32560 dose-dependently reduced ventricular fibrillation (VF) incidence from 19.0 (control) to 9.2 and 1.2 and VF duration from 88.0 s to 34.5 and 2.8 s (all P<0.05, n = 6). KR-32560 also exerted similar effects on reperfusion arrhythmias, except for VPBs. These results indicate that KR-32560 may exert significant cardioprotective effects in ischemia/reperfusion heart injury.
Park
Jung-Woo
JW
Department of Applied Biochemistry, Division of Life Science, College of Biomedical and Health Science, Konkuk University, Chungju 380-701, Korea.
Roh
Hui-Yul
HY
Jung
In-Sang
IS
Yun
Yeo-Pyo
YP
Yi
Kyu-Yang
KY
Yoo
Sung-Eun
SE
Kwon
Suk-Hyung
SH
Chung
Hun-Jong
HJ
Shin
Hwa-Sup
HS
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D002316:Cardiotonic Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology*; D006352:Heart Ventricles; D008297:Male; D015394:Molecular Structure; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013997:Time Factors
D002316:Cardiotonic Agents; D006146:Guanidines; D017923:Sodium-Hydrogen Exchangers; C502305:(5-(2-methoxy-5-chloro-5-phenyl)furan-2-ylcarbonyl)guanidine