U50,488H抗大鼠缺血/再灌注损伤心律失常作用与抑制钠通道电流有关

Anti-arrhythmic effects of U50,488H involving the inhibition of Na^+ current in ischemia/reperfusion rat heart

目的观察κ阿片受体选择性激动剂(U50,488H)对大鼠心脏缺血/再灌注(ischemia and reperfusion,I/R)室性心律失常的影响并探讨其可能的机制。方法观察U50,488H对大鼠I/R整体动物模型血浆肌酸磷酸激酶(CK)、乳酸脱氢酶(LDH)水平的影响;分离正常大鼠心脏,采用Langen-dorff离体心脏灌流方法,预先给予U50,488H(5mmol·L-1)和NE(100μmol·L-1),测定其对血流动力学指标和对心律失常的影响;常规酶解法分离成年大鼠心室肌细胞,采用全细胞膜片钳技术观察U50,488H对钠电流的作用。结果①U50+I/R组血浆中CK和LDH的含量较I/R组明显降低(P<0.01)。②与I/R组相比,给予U50,488H后,心率明显下降(P<0.05)。③对照组偶发早搏,I/R组心律失常发生频率明显增加,与I/R组相比较,I/R+NE组心律失常评分明显增高(P<0.01);如果提前给予U50,488H,发现不仅可以明显降低I/R组缺血和再灌注期间室速和室颤的发生率(P<0.01)及降低I/R组心律失常的评分,而且明显降低I/R+NE组心律失常的评分(P<0.01)。④U50,488H(100μmol·L-1)可以明显降低心室肌细胞的钠电流(P<0.01)。结论κ阿片受体激动剂U50,488H对I/R时的心律失常有拮抗作用,其作用可能是通过抑制心肌细胞的钠电流而实现的。

Aim To investigate the effects of U50, 488H（ a selective K-opioid receptor agonist）on ventricular arrhythmias induced by myocardial isehemia and reperfusion in rats and to elucidate their mechanisms. Methods The contents of CK （creatine phosphokinase） and LDH （ lactate dehydrogenase ） were measured; The isolated heart was perfused using langendorff equipment. Heart rate （HR）, arterial blood pressure （ ABP ）, left ventricular pressure （ LVP ）, cardiac function （ ± dp/dtmax ）, rate of ventricular tachycardia （VT） and ventricular fibrillation（VF） were examined in rats in vitro. The incidence of ventricular arrhythmias and arrhythmia score were also determined; The change of sodium currents （INa） induced by U50, 488H was detected by whole-cell recording mode using patch clamp. Results ① In comparison with I/R group, the contents of CK, LDH in plasma of rats in U50,488H ＋ I/R group were significantly lowered（ P 〈 0. 01 ）. ②Compared with I/R group, Heart rate decrease significantly following U50,488H administration. ③ Compared with normal control group and I/R group, the incidence of ventricular arrhythmias and arrhythmia score were enhanced in I/R ＋ NE group. However, the incidence of ventricular arrhythmias and arrhythmia score were significantly decreased with administration of U50,488H（P 〈0. 01 ）. ④ INa was significantly inhibited by U50,488H （ P 〈 0. 01 ）. Conclusion κ-opioid receptor agonist, U50,488H, which antagonizes the arrhythmias during myocardial ischemia and reperfusion is probably by inhibiting INa.