Protective Activity of Calcium Entry Blockers Against Ouabain Intoxication in Anesthetized Guinea Pigs
Protective Activity of Calcium Entry Blockers Against Ouabain Intoxication in Anesthetized Guinea Pigs
复制标题
钙进入阻滞剂对麻醉豚鼠哇巴因中毒的保护活性
DOI：
10.1097/00005344-198609000-00019
复制
发表时间：
1986
影响因子：
3
通讯作者：
P. V. van Zwieten
中科院分区：
文献类型：
--
作者：
F. Jonkman;H. Boddeke;P. V. van Zwieten
总结：几项研究表明钙在洋地黄诱导的心律失常的发病机制中起核心作用。为了验证这一假设，将钙离子进入阻滞剂硝苯地平、氟桂利嗪、维拉帕米、地尔硫卓和苄普地尔、钙离子进入促进剂Bay K 8644和CaCl 2动脉内预处理对哇巴因诱导的心律失常的影响与目前应用的洋地黄解毒剂苯妥英钠和利多卡因在麻醉（1.5 g/kg i. p.）豚鼠硝苯地平（0.03和0.1 mg/kg）、氟桂利嗪（1和3 mg/kg）和苯妥英（10 mg/kg）预处理使引起毒性ECG变化所需的时间加倍（从10-20分钟增加到20-40分钟）。维拉帕米、地尔硫卓和苄普地尔引起哇巴因毒性轻微但显著降低。CaCl_2（10 mg/kg）预处理可增强哇巴因的毒性作用。上述预处理均未改变ECG参数。Bay K 8644（0.03和0.1mg/kg）可增强哇巴因对室性心律的影响，但可消除哇巴因对房室传导的损害。Bay k 8644本身可增加心率（0.1 mg/kg时从318 ± 11次/min增加至376 ± 6次/min）并缩短PR间期。哇巴因（3 × 10-7 M）预处理后15 min，在电起搏（3 Hz）豚鼠离体左心房中定量钙离子进入阻滞剂的负性肌力作用。其负性肌力作用的大小顺序为硝苯地平>维拉帕米>苄普地尔>地尔硫卓>氟桂利嗪。总之，硝苯地平、氟桂利嗪和苯妥英钠对哇巴因诱导的心律失常表现出明显且同样有效的保护作用。由于没有严重的心血管副作用，氟桂利嗪及其相关化合物可能为强心苷中毒的治疗提供新的治疗可能性。
Summary: Several studies have suggested a central role for calcium in the pathogenesis of digitalis-induced arrhythmias. To test this hypothesis, the effects on ouabain-induced arrhythmia of intraarterial pretreatment with the calcium entry blockers nifedipine, flunarizine, verapamil, diltiazem, and bepridil, the calcium entry promotor Bay K 8644, and CaCl2 were compared with those of the currently applied digitalis antidotes phenytoin and lidocaine in urethane-anesthetized (1.5 g/kg i.p.) guinea pigs. Pretreatment with nifedipine (0.03 and 0.1 mg/kg), flunarizine (1 and 3 mg/kg), and phenytoin (10 mg/kg) doubled the time (from 10–20 to 20–40 min) required to provoke toxic ECG changes. Verapamil, diltiazem, and bepridil caused a slight but significant reduction of ouabain toxicity. Pretreatment with CaCl2 (10 mg/kg) enhanced all toxic effects of ouabain. None of the abovementioned pretreatments as such changed the ECG parameters. Bay k 8644 (0.03 and 0.1 mg/kg) enhanced the effects of ouabain on ventricular rhythm, but abolished the ouabain-induced impairment of AV conduction. Bay k 8644 as such increased heart rate (from 318 ± 11 to 376 ± 6 beats/min at 0.1 mg/kg) and shortened the PR interval. The negative inotropic effects of the calcium entry blockers were quantified in electrically paced (3 Hz) guinea pig isolated left atria 15 min after pretreatment with ouabain (3 x 10-7 M). The rank order of potency for the negative inotropic effect was nifedipine > verapamil > bepridil > diltiazem > flunarizine. In conclusion, nifedipine, flunarizine, and phenytoin showed obvious and equally effective protection against ouabain-induced arrhythmia. Because of the absence of severe cardiovascular side effects, flunarizine and related compounds may offer new therapeutic possibilities in the treatment of intoxication with cardiac glycosides.