title: Pharmacological profile of KR-33028, a highly selective inhibitor of Na+/H+ exchanger.
abstract: We evaluated the cardioprotective effects of 4-cyano (benzo[b]thiophene-2-carbonyl)guanidine (KR-33028), a recently developed inhibitor of the Na+/H+ exchanger (NHE), on hypoxia-induced H9c2 cell death and on perfused rat hearts subjected to ischemia/reperfusion. KR-33028 inhibited in a concentration-dependent manner the recovery from acidosis induced by an NH4Cl prepulse in PS120 fibroblast cells expressing the human NHE-1 isoform (IC50: 2.59 microM). Treatment with KR-33028 (1-10 microM) significantly decreased hypoxia-induced necrotic cell death and apoptotic cell death in H9c2 cells. KR-33028 significantly inhibited hypoxia-induced increases in cytosolic and mitochondrial Ca2+ level and cytochrome c release, and recovered hypoxia-induced Delta psi(m) reduction. In the perfused rat hearts subjected to 30 min of ischemia and 30 min of reperfusion, KR-33028 (1-10 microM) improved cardiac contractility, decreased lactate dehydrogenase release, and increased content of tissue ATP, creatine phosphate and glycogen in a concentration-dependent manner. In addition, KR-33028 did not produce significant acute or subacute toxicity in the rats at doses tested. Our results suggest that a novel NHE-1 inhibitor KR-33028 possesses potent cardioprotective effects with minimal toxicity and that the effects may be mediated by inhibition of intracellular Ca2+ overload and mitochondrial cell death pathway.
authors.affiliation: Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea.
authors.forename: Yi-Sook
authors.initials: YS
authors.lastname: Jung
authors.forename: Mi-Young
authors.initials: MY
authors.lastname: Kim
authors.forename: Mi Jeong
authors.initials: MJ
authors.lastname: Kim
authors.forename: Kwang-Seok
authors.initials: KS
authors.lastname: Oh
authors.forename: Kyu Yang
authors.initials: KY
authors.lastname: Yi
authors.forename: Sunkyung
authors.initials: S
authors.lastname: Lee
authors.forename: Sung-eun
authors.initials: SE
authors.lastname: Yoo
authors.forename: Byung Ho
authors.initials: BH
authors.lastname: Lee
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000643:Ammonium Chloride / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology; D015687:Cell Hypoxia; D002460:Cell Line; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004906:Erythrocyte Count; D005260:Female; D006003:Glycogen / Q000378:metabolism; D006146:Guanidines / Q000378:metabolism / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020287:In Situ Nick-End Labeling; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010477:Perfusion; D010725:Phosphocreatine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000254:growth & development; D013876:Thiophenes / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D006146:Guanidines; C507425:N-(4-cyano-benzo(b)thiophene-2-carbonyl)guanidine; D011956:Receptors, Cell Surface; D017923:Sodium-Hydrogen Exchangers; D013876:Thiophenes; D000643:Ammonium Chloride; D010725:Phosphocreatine; D000255:Adenosine Triphosphate; D006003:Glycogen; D002118:Calcium