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: Yan Lv, Yongkui Ren, Lufan Sun, Shaojun Wang, Minjie Wei, Dalin Jia
• Journal: Cell biochemistry and biophysics (Cell Biochem Biophys) Vol. 66 Issue 2 Pg. 357-63 (Jun 2013) ISSN: 1559-0283 [Electronic] United States
• PMID: 23212178 (Publication Type: Journal Article)

Chemical References

• 2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate
• Anti-Arrhythmia Agents
• Hypoglycemic Agents
• Sodium-Calcium Exchanger
• Thiourea
• Glyburide

Topics

• Animals
• Anti-Arrhythmia Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Diet, High-Fat
• Disease Models, Animal
• Glyburide (pharmacology)
• Hemodynamics (drug effects)
• Hypercholesterolemia (complications)
• Hypoglycemic Agents (pharmacology)
• Male
• Myocardial Reperfusion Injury (complications, drug therapy)
• Rats
• Rats, Wistar
• Sodium-Calcium Exchanger (antagonists & inhibitors, metabolism)
• Thiourea (analogs & derivatives, pharmacology, therapeutic use)