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

Eur J Pharmacol. 2006 Mar 27;535(1-3):220-7. doi: 10.1016/j.ejphar.2006.01.041. Epub 2006 Mar 6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Ammonium Chloride / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Behavior, Animal / drug effects
  • Binding, Competitive
  • Calcium / metabolism
  • Cardiotonic Agents / pharmacology
  • Cell Hypoxia
  • Cell Line
  • Cytosol / drug effects
  • Cytosol / metabolism
  • Dose-Response Relationship, Drug
  • Erythrocyte Count
  • Female
  • Glycogen / metabolism
  • Guanidines / metabolism
  • Guanidines / pharmacology*
  • Heart / drug effects
  • Heart / physiopathology
  • Humans
  • Hydrogen-Ion Concentration
  • In Situ Nick-End Labeling
  • Male
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Myocardial Reperfusion Injury / physiopathology
  • Myocardial Reperfusion Injury / prevention & control
  • Myocardium / metabolism
  • Organ Size / drug effects
  • Perfusion
  • Phosphocreatine / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Cell Surface / metabolism
  • Sodium-Hydrogen Exchangers / antagonists & inhibitors*
  • Sodium-Hydrogen Exchangers / metabolism
  • Spleen / drug effects
  • Spleen / growth & development
  • Thiophenes / metabolism
  • Thiophenes / pharmacology*

Substances

  • Cardiotonic Agents
  • Guanidines
  • N-(4-cyano-benzo(b)thiophene-2-carbonyl)guanidine
  • Receptors, Cell Surface
  • Sodium-Hydrogen Exchangers
  • Thiophenes
  • Ammonium Chloride
  • Phosphocreatine
  • Adenosine Triphosphate
  • Glycogen
  • Calcium