Lemmens-Gruber R, Zilberszac A, Heistracher P
Institute of Pharmacology and Toxicology, University of Vienna, Austria.
Arch Int Pharmacodyn Ther. 1996 Jan-Feb;331(1):46-58.
The association between torsade de pointes and experimentally induced early afterdepolarizations in isolated fibres is well documented. The effect of eight beta-adrenoceptor-blocking drugs (sotalol, nifenalol, acebutolol, dichloroisoproterenol, propranolol, oxprenolol, pindolol, atenolol), and of amiodarone, was studied in isolated spontaneously beating guinea-pig Purkinje fibres by the intracellular microelectrode technique. Phase 3 early afterdepolarizations were initiated by nifenalol hydrochloride (n = 18; 10 mumol/l: 0/18, 40 mumol/l: 3/18, 80 mumol/l: 8/18, 160 mumol/l: 11/18), rac.-(+/-)-sotalol hydrochloride (n = 28; 20 mumol/l: 0/28, 40 mumol/l: 9/28, 80 mumol/l: 20/28), (R)(+)-sotalol hydrochloride (n = 12; 40 mumol/l: 1/12, 80 mumol/l: 4/12), and (S)(-)-sotalol hydrochloride (n = 10, 40 mumol/l: 1/10, 80 mumol/l: 4/10). The arrhythmogenic effect was reversible after a washout period of one hour and early after-depolarizations could be terminated by tetrodotoxin (0.4-1.6 mumol/l, n = 6). Amiodarone only induced early afterdepolarizations at a low extracellular potassium concentration of [K+]o = 1.35 mmol/l (n = 5; 150 mumol/l: 0/5, 300 mumol/l: 1/5). The initiation of early after-depolarizations by sotalol and nifenalol might be induced by an imbalance of sodium inward current and potassium outward currents, and early afterdepolarizations are blocked by tetrodotoxin.
尖端扭转型室速与在离体纤维中实验诱导的早期后除极之间的关联已有充分记载。采用细胞内微电极技术，在离体自发搏动的豚鼠浦肯野纤维中研究了8种β肾上腺素受体阻滞剂（索他洛尔、硝苯洛尔、醋丁洛尔、二氯异丙肾上腺素、普萘洛尔、氧烯洛尔、吲哚洛尔、阿替洛尔）以及胺碘酮的作用。盐酸硝苯洛尔引发了3期早期后除极（n = 18；10 μmol/L：0/18，40 μmol/L：3/18，80 μmol/L：8/18，160 μmol/L：11/18），消旋 -（±）- 盐酸索他洛尔（n = 28；20 μmol/L：0/28，40 μmol/L：9/28，80 μmol/L：20/28），（R）（+）- 盐酸索他洛尔（n = 12；40 μmol/L：1/12，80 μmol/L：4/12），以及（S）（ -）- 盐酸索他洛尔（n = 10，40 μmol/L：1/10，80 μmol/L：4/10）。经过1小时的洗脱期后，致心律失常作用是可逆的，早期后除极可被河豚毒素（0.4 - 1.6 μmol/L，n = 6）终止。胺碘酮仅在细胞外低钾浓度[K⁺]o = 1.35 mmol/L时诱导早期后除极（n = 5；150 μmol/L：0/5，300 μmol/L：1/5）。索他洛尔和硝苯洛尔引发早期后除极可能是由内向钠电流和外向钾电流失衡所致，且早期后除极可被河豚毒素阻断。
