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: Yi-Sook Jung, Mi-Young Kim, Mi Jeong Kim, Kwang-Seok Oh, Kyu Yang Yi, Sunkyung Lee, Sung-eun Yoo, Byung Ho Lee
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 535 Issue 1-3 Pg. 220-7 (Mar 27 2006) ISSN: 0014-2999 [Print] Netherlands
• PMID: 16516883 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• 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, metabolism)
• Dose-Response Relationship, Drug
• Erythrocyte Count
• Female
• Glycogen (metabolism)
• Guanidines (metabolism, pharmacology)
• Heart (drug effects, physiopathology)
• Humans
• Hydrogen-Ion Concentration
• In Situ Nick-End Labeling
• Male
• Mitochondria (drug effects, metabolism)
• Myocardial Reperfusion Injury (physiopathology, prevention & control)
• Myocardium (metabolism)
• Organ Size (drug effects)
• Perfusion
• Phosphocreatine (metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptors, Cell Surface (metabolism)
• Sodium-Hydrogen Exchangers (antagonists & inhibitors, metabolism)
• Spleen (drug effects, growth & development)
• Thiophenes (metabolism, pharmacology)