CPU0213, a novel endothelin type A and type B receptor antagonist, protects against myocardial ischemia/reperfusion injury in rats.

Abstract

The efficacy of endothelin receptor antagonists in protecting against myocardial ischemia/reperfusion (I/R) injury is controversial, and the mechanisms remain unclear. The aim of this study was to investigate the effects of CPU0123, a novel endothelin type A and type B receptor antagonist, on myocardial I/R injury and to explore the mechanisms involved. Male Sprague-Dawley rats weighing 200-250 g were randomized to three groups (6-7 per group): group 1, Sham; group 2, I/R + vehicle. Rats were subjected to in vivo myocardial I/R injury by ligation of the left anterior descending coronary artery and 0.5% sodium carboxymethyl cellulose (1 mL/kg) was injected intraperitoneally immediately prior to coronary occlusion. Group 3, I/R + CPU0213. Rats were subjected to identical surgical procedures and CPU0213 (30 mg/kg) was injected intraperitoneally immediately prior to coronary occlusion. Infarct size, cardiac function and biochemical changes were measured. CPU0213 pretreatment reduced infarct size as a percentage of the ischemic area by 44.5% (I/R + vehicle: 61.3 ± 3.2 vs I/R + CPU0213: 34.0 ± 5.5%, P < 0.05) and improved ejection fraction by 17.2% (I/R + vehicle: 58.4 ± 2.8 vs I/R + CPU0213: 68.5 ± 2.2%, P < 0.05) compared to vehicle-treated animals. This protection was associated with inhibition of myocardial inflammation and oxidative stress. Moreover, reduction in Akt (protein kinase B) and endothelial nitric oxide synthase (eNOS) phosphorylation induced by myocardial I/R injury was limited by CPU0213 (P < 0.05). These data suggest that CPU0123, a non-selective antagonist, has protective effects against myocardial I/R injury in rats, which may be related to the Akt/eNOS pathway.

• Authors: Z Y Wang, W Zhang, X Z Li, Y Han, Y P Chen, Z Liu, L P Xie, Y Ji, X Lu
• Journal: Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas (Braz J Med Biol Res) Vol. 44 Issue 11 Pg. 1148-55 (Nov 2011) ISSN: 1414-431X [Electronic] Brazil
• PMID: 21915473 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CPU0213
• Cardiotonic Agents
• Endothelin A Receptor Antagonists
• Endothelin B Receptor Antagonists
• Pyrazoles
• Nitric Oxide Synthase Type III
• Proto-Oncogene Proteins c-akt

Topics

• Analysis of Variance
• Animals
• Cardiotonic Agents (pharmacology)
• Disease Models, Animal
• Endothelin A Receptor Antagonists
• Endothelin B Receptor Antagonists
• Male
• Myocardial Reperfusion Injury (drug therapy, prevention & control)
• Nitric Oxide Synthase Type III (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyrazoles (pharmacology)
• Random Allocation
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)