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Pharmacological profile of KR-33028, a highly selective inhibitor of Na+/H+ exchanger.

Authors
Jung, YS; Kim, MY; Kim, MJ; Oh, KS; Yi, KY; Lee, S; Yoo, SE; Lee, BH
Citation
European journal of pharmacology, 535(1-3):220-227, 2006
Journal Title
European journal of pharmacology
ISSN
0014-29991879-0712
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.
MeSH terms
Adenosine Triphosphate/metabolismAmmonium Chloride/pharmacologyAnimalsApoptosis/drug effectsBehavior, Animal/drug effectsBinding, CompetitiveCalcium/metabolismCardiotonic Agents/pharmacologyCell HypoxiaCell LineCytosol/drug effectsCytosol/metabolismDose-Response Relationship, DrugErythrocyte CountFemaleGlycogen/metabolismGuanidines/metabolismGuanidines/pharmacology*Heart/drug effectsHeart/physiopathologyHumansHydrogen-Ion ConcentrationIn Situ Nick-End LabelingMaleMitochondria/drug effectsMitochondria/metabolismMyocardial Reperfusion Injury/physiopathologyMyocardial Reperfusion Injury/prevention & controlMyocardium/metabolismOrgan Size/drug effectsPerfusionPhosphocreatine/metabolismRatsRats, Sprague-DawleyReceptors, Cell Surface/metabolismSodium-Hydrogen Antiporter/antagonists & inhibitors*Sodium-Hydrogen Antiporter/metabolismSpleen/drug effectsSpleen/growth & developmentThiophenes/metabolismThiophenes/pharmacology*
DOI
10.1016/j.ejphar.2006.01.041
PMID
16516883
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Journal Papers > School of Medicine / Graduate School of Medicine > Physiology
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