AMP579与腺苷对大鼠和豚鼠心室肌钾离子或钠离子通道作用的比较

Action of AMP579 and adenosine on potassium or sodium ionic channels in isolated rat and guinea pig ventricular myocytes

目的研究AMP579和腺苷对钾离子与钠离子通道的影响及其作用机制,比较它们对负性变力及抗心律失常作用的离子机制。方法采用膜片钳全细胞记录模式记录大鼠和豚鼠心室肌细胞离子通道电流。结果腺苷对大鼠心室肌瞬时外向钾电流(Ito)的激动作用强于AMP579,腺苷和AMP579的EC50值分别为2.33与8.32μmol.L-1(P<0.05);两者激动Ito的作用均可被腺苷A1受体阻滞剂PD116948阻断,表明其作用机制均是通过腺苷A1受体介导的。腺苷对豚鼠心室肌延迟整流钾电流(IK)的抑制作用强于AMP579,腺苷和AMP579的IC50值分别为1.21与2.31μmol.L-1(P<0.05);AMP579对内向整流钾电流(IK1)的抑制作用强于腺苷,AMP579和腺苷的IC50值分别为4.15与20.7μmol.L-1(P<0.01)。AMP579和腺苷对大鼠心室肌钠电流(INa)的抑制作用相似,其IC50值分别为9.46与6.23μmol.L-1。结论腺苷对大鼠心室肌Ito的激动作用强于AMP579,两者对Ito的作用机制均是通过腺苷A1受体介导的。AMP579对IK1的抑制作用强于腺苷,而腺苷对IK的抑制作用强于AMP579,两者对INa的抑制作用相似,这些离子机制与两者发挥负性变力与抗心律失常作用有关系。

Aim To study the effect of AMP579 and adenosine on potassium ionic （ K^＋ ） or sodium ionic （Na^＋ ） channels and to elucidate ionic mechanisms underlying negative inotropic and antiarrhythmic effects of AMP579 and adenosine. Methods Ionic channel currents of rat and guinea pig ventricular myocytes were recorded by patch clamp technique in whole-cell configuration. Results Adenosine showed a stronger activating effect on transient outward K^＋ current （Ito） than AMP579, EC50 of adenosine and AMP579 were 2.33 and 8.32μmol· L^-1, respectively （P 〈0.05）. An adenosine A1 receptor blocker, 1,3-dipropyl-8-cyclopentylxanthine （PD116948）, can abolish the effects of AMP579 and adenosine on Ito demonstrating that the effect is mediated by adenosine A1 receptor. Adenosine exerted a more obvious inhibitory effect on delayed rectifier K^＋ current （IK） than AMP579. IC50 of adenosine and AMP579 were 1.21 and 2.31μmol·L^-1, respectively （P 〈0.05）. AMP579 had a more powerful inhibitory effect on inward rectifier K ^＋ current （IK,） than adenosine. IC50 of AMP579 and adenosine were 4. 15 and 20.7μmol· L^-1 , repectively （P 〈0.01 ）. AMP579 and adenosine exerted a similar inhibitory effect on fast inward Na^＋ current （ INa ） , IC50 of AMP579 and adenosine were 9.46 and 6. 23 μmol·L^-1 , respectively （P 〉 0.05）. Conclusion Adenosine showed a stronger activating effect on Ito than AMP579, however, the mechanism of AMP579 and adenosine activating Ito was mediated by adenosine A1 receptor. AMP579 has a more powerful inhibitory effect on IK1, and less inhibitory effect on IK than adenosine. Both drugs have a similar inhibitory effect on INa. The negative inotropic and antiarrhythmic effects are related to these ionic mechanisms.