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Cardioprotective effects of the novel Na+/H+ exchanger-1 inhibitor KR-32560 in a perfused rat heart model of global ischemia and reperfusion: Involvement of the Akt-GSK-3beta cell survival pathway and antioxidant enzyme.

Abstract
To investigate the cardioprotective effects and mechanism of action of KR-32560 {[5-(2-methoxy-5-fluorophenyl)furan-2-ylcarbonyl]guanidine}, a newly synthesized NHE-1 inhibitor, we evaluated the effects of KR-32560 on cardiac function in a rat model of ischemia/reperfusion (I/R)-induced heart injury as well as the role antioxidant enzymes and pro-survival proteins play these observed effects. In isolated rat hearts subjected to 25 min of global ischemia followed by 30 min of reperfusion, KR-32560 (3 and 10 microM) significantly reversed the I/Rinduced decrease in left ventricular developed pressure and increase in left ventricular enddiastolic pressure. In rat hearts reperfused for 30 min, KR-32560 (10 microM) significantly decreased the malondialdehyde content while increasing the activities of both glutathione peroxidase and catalase, two important antioxidant enzymes. Western blotting analysis of left ventricles subjected to I/R showed that KR-32560 significantly increased phosphorylation of both Akt and GSK-3beta in a dose-dependent manner, with no effect on the phosphorylation of eNOS. These results suggest that KR-32560 exerts potent cardioprotective effects against I/Rinduced rat heart injury and that its mechanism involves antioxidant enzymes and the Akt-GSK-3beta cell survival pathway.
AuthorsIn-Sang Jung, Sung-Hun Lee, Min-Kyu Yang, Jung-Woo Park, Kyu-Yang Yi, Sung-Eun Yoo, Suk-Hyung Kwon, Hun-Jong Chung, Wahn-Soo Choi, Hwa-Sup Shin
JournalArchives of pharmacal research (Arch Pharm Res) Vol. 33 Issue 8 Pg. 1241-51 (Aug 2010) ISSN: 1976-3786 [Electronic] Korea (South)
PMID20803128 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antioxidants
  • Cardiotonic Agents
  • Guanidines
  • KR-32560
  • Sodium-Hydrogen Exchangers
  • growth factor-activatable Na-H exchanger NHE-1
  • Malondialdehyde
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, rat
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3
Topics
  • Animals
  • Antioxidants (metabolism)
  • Blotting, Western
  • Cardiotonic Agents (administration & dosage, pharmacology)
  • Cell Survival (drug effects)
  • Dose-Response Relationship, Drug
  • Glycogen Synthase Kinase 3 (metabolism)
  • Glycogen Synthase Kinase 3 beta
  • Guanidines (administration & dosage, pharmacology)
  • Male
  • Malondialdehyde (metabolism)
  • Myocardial Reperfusion Injury (physiopathology)
  • Proto-Oncogene Proteins c-akt (metabolism)
  • Rats
  • Rats, Sprague-Dawley
  • Sodium-Hydrogen Exchangers (antagonists & inhibitors)
  • Ventricular Dysfunction, Left (prevention & control)

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