Novel lactam type pyridine derivatives improves myocardium dysfunction derived from ischemic injury

The extended acute myocardial ischemia (AMI) results in cardiac myocytes death. In the present study, we show that lactam pyridine derivative, SK-D80375, have the effects on cell survival in hypoxic cardiomyocytes and might be used as an anti-ischemic drug. The lactam pyridine derivatives are inhibitors of the late sodium current, which decreases sodium-dependent intracellular calcium overload in ischemia/reperfusion-injured hearts. We found that pretreatment with SK-D80375 significantly decreased the level of intracellular Ca²⁺and the expression level of the Na⁺-Ca²⁺exchanger by 39±2.5% and 19±0.5%, respectively in hypoxic cardiomyocytes compared to untreated controls. In addition, the expression level of sarcoplasmic reticulum Ca²⁺ATPase 2a was significantly increased by 37±1.5% in SK-D80375-treated hypoxic cardiomyocytes compared to untreated controls. The induction of Hsp70 was observed in SK-D80375-treated hypoxic cardiomyocytes with dose-dependent manner and the highest level of Hsp70 was induced at the concentration of 2.5 μM SK-D80375. The echocardiographic analysis showed that heart function was significantly improved in SK-D80375-injected ischemic hearts. These results demonstrate that lactam pyridine derivative, SK-D80375, have beneficial effects on hypoxia-induced cell death, therefore, might be used as a novel anti-ischemia drug.