Fossa Anthony A, Wisialowski Todd, Wolfgang Eric, Wang Ellen, Avery Michael, Raunig David L, Fermini Bernard
Pfizer Global Research and Development, Eastern Point Rd., Bldg. 118, MS 4036 Groton, CT 06340, USA.
Eur J Pharmacol. 2004 Feb 20;486(2):209-21. doi: 10.1016/j.ejphar.2003.12.028.
Beat-to-beat alternations of the cardiac monophasic action potential, known as electrical alternans, were studied at drug concentrations that have known arrhythmogenic outcomes. Electrical alternans were elicited from the heart of anesthetized guinea pigs, both in the absence and presence of drugs that inhibit the delayed rectifier K(+) channel encoded by the human ether a-go-go related-gene (HERG), and are associated with the fatal arrhythmia, Torsade de Pointes. Two other HERG inhibiting drugs not associated with Torsade de Pointes were also studied. At concentrations known to be proarrhythmic, E-4031 and bepridil increased mean alternans 10 and 40 ms at pacing frequencies </=160 ms. Terfenadine and cisapride both increased mean alternans up to 20 and 21 ms, respectively, at pacing frequencies of </=150 ms. On the other hand, verapamil and risperidone showed no increase in mean alternans while risperidone significantly reduced alternans at concentrations up to 74 times its therapeutic level. The magnitude of effect on rate-dependent alternans may allow the differentiation of proarrhythmia and non-arrhythmic HERG blockers at clinically relevant concentrations.
在已知有致心律失常结果的药物浓度下，研究了心脏单相动作电位的逐搏交替现象，即电交替现象。在麻醉豚鼠心脏中引发电交替现象，分别在不存在和存在抑制由人类醚 - 去极化相关基因（HERG）编码的延迟整流钾通道的药物的情况下进行研究，这些药物与致命性心律失常尖端扭转型室速有关。还研究了另外两种与尖端扭转型室速无关的HERG抑制药物。在已知可致心律失常的浓度下，E - 4031和苄普地尔在起搏频率≤160毫秒时使平均交替现象增加10毫秒和40毫秒。特非那定和西沙必利在起搏频率≤150毫秒时分别使平均交替现象增加至20毫秒和21毫秒。另一方面，维拉帕米和利培酮未显示平均交替现象增加，而利培酮在浓度高达其治疗水平74倍时显著降低了交替现象。在临床相关浓度下，对频率依赖性交替现象的影响程度可能有助于区分致心律失常和非致心律失常的HERG阻滞剂。
