DMA选择性激动心力衰竭大鼠离体心室肌细胞Na^(+)/Ca^(2+)交换体提高心肌变力

DMA enhances the myocardial inotropism by selective and agonistic effects on Na^(+)/Ca^(2+)exchange currents in isolated ventricular myocytes of rats with heart failure

目的二甲基氨氯吡咪(DMA)作为强效的选择性Na^(+)/H^(+)交换体抑制剂,可以特异性增强大鼠心肌细胞的Na^(+)/Ca^(2+)交换(NCX)电流。NCX是治疗心力衰竭(心衰)的一个有潜力的靶点。本研究拟验证DMA是否增强NCX电流(INa/Ca),诱导Ca^(2+)内流,产生对心衰大鼠心室肌细胞的正性肌力作用。方法采用腹主动脉缩窄法诱导大鼠心衰模型,胶原酶法急性分离正常和心衰大鼠心室肌细胞;采用膜片钳全细胞记录方法测定细胞的I_(Ca-L),I_(Na),I _(K1),I_(to),和I_(Na/Ca),膜电流大小以电流强度表示,在正常和心衰大鼠离体心室肌细胞中观察DMA对主要离子电流的影响。结果DMA(0.1、0.3、1和3μmol/L)对正常和心衰大鼠心室肌细胞NCX内向和外向电流均呈浓度依赖性增加,心衰大鼠心室肌细胞在电位+50mV的外向INa/Ca密度分别增大了(10.78±4.73)%、(31.47±5.47)%、(55.60±16.84)%、(75.01±19.74)%,在电位-100mV的内向INa/Ca密度分别增大了(19.00±6.29)%、(33.51±20.17)%、(55.49±22.56)%、(94.77±15.75)%。DMA诱导的向内NCX电流的增强作用大于对外向NCX电流作用,但DMA对ICa-L、INa、I K1和Ito无明显影响。结论DMA可以双向激动心衰大鼠心肌细胞,DMA的正性肌力作用可能与INa/Ca升高相关。DMA作为一种新的NCX激动剂,为治疗心衰提供新思路。

Objectives 5-(N,N-dimethyl)-amiloride(DMA)is an amiloride derivative with enhanced potency and selectivity as an inhibitor of Na^(+)/H^(+)exchange and enhances the Na^(+)/Ca^(2+)exchange(NCX)current in rat cardiomyocytes.NCX is an attractive target for the treatment of heart failure(HF).The aim of this study was to verify whether NCX current(I_(Na/Ca))augmentation induces Ca^(2+)influx and contributes to the positive inotropic effect of DMA on rat ventricular myocytes.Methods HF was induced in rats via abdominal aortic banding surgery.Acute isolation of ventricular myocytes from normal and HF rats by collagenase.I_(Ca-L),I_(Na),I_(K1),I_(to),and I_(Na/Ca)were recorded by whole-cell patch-clamping.The membrane currents were expressed by current intensity.The effects of DMA on the main ion currents were observed in isolated ventricular myocytes of normal and HF rats.Results DMA increased the outward and inward I_(Na/Ca)in a concentration-dependent manner in ventricular cells of normal and HF rats.DMA(0.1,0.3,1,and 3μmol/L)increased outward I_(Na/Ca) density of HF rat ventricular myocytes by(19.00±6.29)%,(33.51±20.17)%,(55.49±22.56)%,(94.77±15.75)%at the potential+50mV,DMA increased inward I_(Na/Ca) density of HF rat ventricular myocytes by(10.78±4.73)%,(31.47±5.47)%,(55.60±16.84)%,(75.01±19.74)%at the potential-100mV.The increased inward NCX current induced by DMA was stronger than the outward current,although DMA had no apparent effects on I_(Ca-L),I_(Na),I_(K1),and I_(to).Conclusion DMA had a stimulating effect on reversed mode NCX performance,and the increase in I_(Na/Ca) might contribute to the positive inotropism of DMA.These findings suggest that DMA,as a novel agonist of NCX,may be beneficial in the treatment of HF patients.