二乙基二硫代氨基甲酸钠对二氧化硫衍生物引起的心肌细胞钠电流增大的增强效应

ENHANCING EFFECTS OF DIETHYLDITHIOCARBAMATE ON INCREASING I_(Na) OF Na^+ CHANNELS BY SULFUR DIOXIDE DERIVATIVE IN THE VENTRICULAR MYOCYTES

超氧化物歧化酶(superoxide dismutase,SOD)是生物体内专一的过氧自由基(superoxide anions,O2.-)清除剂,而二乙基二硫代氨基甲酸钠(diethyldithiocarbamate,DDC)则是公认的Cu,Zn-SOD的抑制剂。采用全膜片钳技术研究了DDC对二氧化硫(sulfur dioxide,SO2)衍生物引起的大鼠心肌细胞钠电流增大效应的作用,以期更进一步揭示SO2的毒性机理。结果表明:SO2衍生物对SOD活性无显著影响,SO2衍生物存在时,DDC仍可以显著降低SOD的活性。DDC(10￣100 mmol/L)剂量依赖性地增大钠电流(INa),半数效应浓度为(19.85±0.95)mmol/L。将20 mmol/L的DDC与10μmol/L的SO2衍生物同时作用于心肌细胞,INa仍表现为电压依赖性的增大,并使INa的电压依赖性激活曲线显著地向负电压方向移动,稳态失活曲线向正电压方向移动,差异极其显著。这表明DDC增强了SO2衍生物对心肌细胞钠电流的增大效应,提示SO2衍生物引起的大鼠心肌细胞毒性主要是通过自由基,特别是O2.-氧化损伤实现的。

Superoxide dismutase （SOD） is an important free radical scavenger, which could scavenge excessive O2- in vivo. Diethyldithiocarbamate （DDC） has been used extensively as an inhibitor of Cu,Zn-SOD. In order to probe into the mechanism of SO2 on cardiovascular system, the enhancing effects of DDC on increasing INa of Na^＋ channels by sulfur dioxide derivatives in the ventricular myocytes were studied using the whole cell patch-clamp technique. The results showed that SO2 derivatives had no significant effect on SOD activity, but the addition of DDC to the SO2 derivatives-containing medium led to significant inhibition of SOD. DDC increased sodium current （INa） in a concentration-dependent manner, the concentration of DDC for half-maximum increase was （19.85±0.95）mmol/L. 10 μmol/L SO2 derivatives and 20 mmol/L DDC significantly shifted voltage-dependent activation curve of INa toward the more negative potential and steady-state inactivation curve to more positive potentials. These results indicated DDC could enhance the effects of increasing INa of Na^＋ channels by SO2 derivatives, and suggested that the toxicity of SO2 derivatives on ventricular myocytes of rat was indticed by free radical especially O2^-.