Protective effects of SEA0400, a novel and selective inhibitor of the Na+/Ca2+ exchanger, on myocardial ischemia-reperfusion injuries.

Abstract

The Na(+)/Ca(2+) exchanger (NCX) is involved in myocardial ischemia-reperfusion injuries. We examined the effects of 2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400), a potent and selective inhibitor of NCX, on myocardial ischemia-reperfusion injury models. In canine cardiac sarcolemmal vesicles and rat cardiomyocytes, SEA0400 potently inhibited the Na(+)-dependent 45Ca(2+) uptake with an IC(50) value of 90 and 92 nM, compared with 2-[2-[4-(4-nitrobenzyloxy)phenyl]isothiourea (KB-R7943, 7.0 and 9.5 microM), respectively. In rat cardiomyocytes, SEA0400 (1 and 3 microM) attenuated the Ca(2+) paradox-induced cell death. In isolated rat Langendorff hearts, SEA0400 (0.3 and 1 microM) improved the cardiac dysfunction induced by low-pressure perfusion followed by normal perfusion. In anesthetized rats, SEA0400 (0.3 and 1 mg/kg, i.v.) reduced the incidence of ventricular fibrillation and mortality induced by occlusion of the left anterior descending coronary artery followed by reperfusion. These results suggest that SEA0400 is a most potent NCX inhibitor in the heart and that it has protective effects against myocardial ischemia-reperfusion injuries.

• Authors: Kenzo Takahashi, Teisuke Takahashi, Taizo Suzuki, Michihito Onishi, Yu Tanaka, Akiko Hamano-Takahashi, Tomomi Ota, Kazuya Kameo, Toshio Matsuda, Akemichi Baba
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 458 Issue 1-2 Pg. 155-62 (Jan 01 2003) ISSN: 0014-2999 [Print] Netherlands
• PMID: 12498920 (Publication Type: Journal Article)

Chemical References

• 2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate
• Aniline Compounds
• Anti-Arrhythmia Agents
• Guanidines
• Phenyl Ethers
• SEA 0400
• Sodium-Calcium Exchanger
• Sulfones
• cariporide
• Thiourea
• Calcium

Topics

• Aniline Compounds (pharmacology)
• Animals
• Anti-Arrhythmia Agents (pharmacology)
• Arrhythmias, Cardiac (physiopathology, prevention & control)
• Calcium (metabolism, pharmacokinetics)
• Cell Survival (drug effects)
• Cells, Cultured
• Dogs
• Guanidines (pharmacology)
• Heart (drug effects, physiopathology)
• In Vitro Techniques
• Male
• Myocardial Reperfusion Injury (physiopathology, prevention & control)
• Myocardium (metabolism)
• Myocytes, Cardiac (cytology, drug effects, metabolism)
• Phenyl Ethers (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Rats, Wistar
• Sarcolemma (drug effects, metabolism)
• Sodium-Calcium Exchanger (antagonists & inhibitors, metabolism)
• Sulfones (pharmacology)
• Thiourea (analogs & derivatives, pharmacology)