title: Protective effect of Na(+)/Ca (2+) exchange blocker KB-R7943 on myocardial ischemia-reperfusion injury in hypercholesterolemic rats.
abstract: Reverse-mode activation of the Na(+)/Ca(2+) exchanger (NCX) during reperfusion following ischemia contributes to Ca(2+) overload and cardiomyocyte injury. KB-R7943, a selective reverse-mode NCX inhibitor, reduces lethal reperfusion injury under non-ischemic conditions. However, the effectiveness of this compound under ischemic conditions is unclear. In the present study, we studied the effects of KB-R7943 in an animal model of hyperlipidemia. We further assessed whether the K ATP (+) channels are involved in potential protective mechanisms of KB-R7943. Twelve rats were fed normal chow, while 48 animals were fed a high cholesterol diet. The hearts from the control and hypercholesterolemic rats were subjected to 25 min of global ischemia followed by a 120-min reperfusion. Before this, hearts from hypercholesterolemic rats either received no intervention (cholesterol control group) or were pre-treated with 1 μM KB-R7943 and 0.3 μM of K ATP (+) blocker glibenclamide or glibenclamide alone. The infarction sizes (triphenyltetrazolium assay) were 35 ± 5.0 % in the control group, 46 ± 8.7 % in the cholesterol control group (p < 0.05 vs. control group), 28.6 ± 3.3 % in the KB-R7943 group (p < 0.05 vs. cholesterol control group), 44 ± 5 % in the KB-R7943 and glibenclamide group, and 47 ± 8.5 % in the glibenclamide group (p < 0.05 vs. control group). Further, KB-R7943 attenuated the magnitude of cell apoptosis (p < 0.05 vs. cholesterol control group). These beneficial effects were abolished by glibenclamide. In conclusion, diet-induced hypercholesterolemia enhances myocardial injury. Selective reverse-mode NCX inhibitor KB-R7943 reduces the infarction size and apoptosis in hyperlipidemic animals through the activation of K ATP (+) channels.
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of China Medical University, 155th North of Nanjing Street, Heping District, Shenyang, 110001, Liaoning Province, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lv
authors.forename: Yongkui
authors.initials: Y
authors.lastname: Ren
authors.forename: Lufan
authors.initials: L
authors.lastname: Sun
authors.forename: Shaojun
authors.initials: S
authors.lastname: Wang
authors.forename: Minjie
authors.initials: M
authors.lastname: Wei
authors.forename: Dalin
authors.initials: D
authors.lastname: Jia
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005905:Glyburide / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D006937:Hypercholesterolemia / Q000150:complications*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000188:drug therapy*; D051381:Rats; D017208:Rats, Wistar; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D000889:Anti-Arrhythmia Agents; D007004:Hypoglycemic Agents; D019831:Sodium-Calcium Exchanger; D013890:Thiourea; D005905:Glyburide