| Coronary heart disease will be the leading cause of death world-wide in 2020, predicted by WHO. After an acute myocardial infarction, early and successful myocardial reperfusion with the use of thrombolytic therapy, primary percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) is the most effective strategy for reducing the size of a myocardial infarct and improving the clinical outcome. The process of restoring blood flow to the ischemic myocardium, however, can induce injury. This phenomenon, termed myocardial reperfusion injury, can paradoxically reduce the beneficial effects of myocardial reperfusion.Endothelin (ET) is a vasoconstrictive peptide isolated from endothelial cells. ET-1 is the most prominent isoform in the cardiovascular system. ET-1 exerts its biological effect via endothelin type A receptors (ET_A receptors) and endothelin type B receptors (ET_B receptors). It affects the physiology and pathophysiology of many systems of the body, especially the cardiovascular system.More and more evidences demonstrate plasma ET-1 levels increased after ischemia-reperfusion (I/R) injury in both clinic studies and animal studies. Endothelin-1 is associated with no-reflow and increased long-term mortality in a high-risk ST-elevation myocardial infarction (STEMI) population reperfused by primary PCI. These results indicate ET-1 plays an important role in I/R injury. However, the role of ET-1 in the ischemic heart appears more complex. Most data suggest ET receptor antagonists have beneficial effect in I/R injury. However, other studies have failed to demonstrate the protection. CPU0213 is a novel ET_A/ET_B antagonist. It has been reported that CPU0213 improves pulmonary arteriolar remodeling of monocrotaline-induced pulmonary hypertension in rats, ameliorates diabetic cardiac insufficiency, and attenuates diabetic nephropathy. The effects of CPU0213 on myocardial I/R injury has not been investigated entirely. Objectives: To investigate the effects of CPU0123 on myocardial I/R injury and to explore the mechanisms.Methods: Rats were randomized to three groups(6-7 rats/group): Sham, I/R+vehicle, I/R+CPU0213. In the I/R+CPU0213 group, rats were subjected to 30 min myocardial ischemia by occlusion of the left anterior descending coronary artery (LAD) and CPU0213 was intraperitoneally injected immediately prior to coronary occlusion. of ischemia. Biochemical estimation and cardiac function was evaluated after 6h reperfusion, infarct size was assessed after 24h reperfusion. Western blots for endothelial nitric oxide synthase (eNOS) and protein kinase B (Akt) were performed in ischemic myocardium.Results: CPU0213 administration significantly decreased infarct size by 44.53% ( I/R + vehicle: 61.30±3.22% vs. I/R + CPU0213: 34.00±5.47%, P<0.05), compared with the I/R+vehicle group. Ejection fraction and fractional shortening in I/R+CPU0213 group were also significantly increased by 17.2% (I/R + vehicle: 58.42±2.83% vs. I/R + CPU0213: 68.45±2.17%, P<0.05) and 27.4% (I/R + vehicle: 26.6±1.57% vs. I/R + CPU0213: 33.94±1.71%, P<0.01), respectively, compared with I/R+vehicle group. CPU0213 corrected elevated plasma ET-1 levels induced by I/R injury and decreased CK (creatine kinase), LDH (lactic dehydrogenase) activity in serum. Moreover, I/R injury increased myocardial inflammation and oxidative stress which is inhibited by CPU0213. Western blots showed that reduction in Akt and eNOS phosphorylation induced by I/R injury is limited by CPU0213.Conclusions: CPU0123 has protective effects against myocardial I/R injury in rats, and this protection may be related to the Akt/eNOS pathway. The data suggest that CPU0213 may be a promising strategy for treatment of myocardial I/R injury.
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