ISOPROTERENOL ANTAGONIZES PROLONGATION OF REFRACTORY PERIOD BY THE CLASS-III ANTIARRHYTHMIC AGENT E-4031 IN GUINEA-PIG MYOCYTES - MECHANISM OF ACTION
ISOPROTERENOL ANTAGONIZES PROLONGATION OF REFRACTORY PERIOD BY THE CLASS-III ANTIARRHYTHMIC AGENT E-4031 IN GUINEA-PIG MYOCYTES - MECHANISM OF ACTION
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DOI：
10.1161/01.res.68.1.77
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发表时间：
1991-01-01
影响因子：
20.1
通讯作者：
SIEGL, PKS
中科院分区：
文献类型：
--
作者：
SANGUINETTI, MC;JURKIEWICZ, NK;SIEGL, PKS
本文研究了异丙肾上腺素（ISO）阻止Ⅲ类抗心律失常药E-4031延长动作电位时程（APD）和不应期（RP）的机制。E-4031（1 μ M）使RP增加50%，对豚鼠心脏分离的乳头肌的收缩力无影响。ISO（1 μ M）的收缩力增加了5倍以上，RP下降了25%。用ISO预处理肌肉可防止E-4031延长RP。5 μ M E-4031对离体豚鼠心室肌细胞APD的延长作用也可被1 μ M ISO预先暴露的细胞所拮抗。采用抽吸式微电极电压钳技术，在离体心肌细胞上测量瞬时电流和延迟整流钾电流I（K）。电流测量响应于225毫秒的去极化脉冲从-40 mV的保持电位。先前的研究表明，这些细胞中的I（K）是由两种不同的外向K+电流I（Ks）和I（Kr）（被E-4031特异性阻断）激活引起的。ISO使I（Ks）的幅度增加一倍，但对I（Kr）无显著影响。瞬时电流（推定为Cl-电流）也被ISO加倍，但不受E-4031的影响。ISO增加了I（Ks）和瞬时电流的电导，导致RP降低。在ISO存在下，E-4031对APD和RP的影响较小，这是由于I（Kr）相对于增强的复极化电流的贡献较小。
The mechanism by which isoproterenol (ISO) prevents the prolongation of action potential duration (APD) and refractory period (RP) by the class III antiarrhythmic agent E-4031 was studied. E-4031 (1-mu-M) increased RP by 50% with no effect on contractile force in papillary muscles isolated from guinea pig heart. ISO (1-mu-M) increased force of contraction more than fivefold and decreased RP by 25%. The prolongation of RP by E-4031 was prevented by pretreatment of muscles with ISO. The prolongation of APD in isolated guinea pig ventricular myocytes by 5-mu-M E-4031 also was antagonized by prior exposure of the cells to 1-mu-M ISO. Instantaneous currents and delayed rectifier K+ currents, I(K), were measured in isolated myocytes using the suction microelectrode voltage-clamp technique. Currents were measured in response to 225-msec depolarizing pulses from a holding potential of - 40 mV. Previous studies have demonstrated that I(K) in these cells results from activation of two distinct outward K+ currents, I(Ks) and I(Kr) (specifically blocked by E-4031). ISO doubled the magnitude of I(Ks) without significant effect on I(Kr). The instantaneous current, putatively identified as a Cl- current, also was doubled by ISO but was unaffected by E-4031. The augmented conductance of I(Ks) and instantaneous current by ISO results in a decrease in RP. The small effect of E-4031 on APD and RP in the presence of ISO results from the smaller contribution of I(Kr) relative to the augmented repolarizing currents.