Shpak Beni, Gofman Yana, Shpak Chagit, Hiller Reuben, Boyman Liron, Khananshvili Daniel
Department of Physiology and Pharmacology, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv 69978, Israel.
Eur J Pharmacol. 2006 Dec 28;553(1-3):196-204. doi: 10.1016/j.ejphar.2006.09.014. Epub 2006 Sep 23.
Previous studies demonstrated that the purified endogenous inhibitor (NCX(IF)) of the cardiac Na(+)/Ca(2+) exchanger (NCX1) has the capacity to modulate cardiac muscle contractility. Here, we tested the effects of purified NCX(IF) on arrhythmias induced by ouabain in the atria and ventricle strips of guinea pig. For the sake of comparison NCX(IF) was compared to lidocaine and KB-R7943. In the ventricle strip, NCX(IF) ( approximately 10 U/ml) results in rapid, complete and stable inhibition of ouabain-induced arrhythmias (the inhibition of arrhythmia is not followed by revival of irregular contractions). Under similar experimental conditions the atria strips require somewhat higher doses of NCX(IF) (25-50 U/ml) for complete suppression of arrhythmia. In the atria strip, NCX(IF) (10-25 U/ml) increases the threshold dose (1 microM) of ouabain for arrhythmia onset 2.2+/-0.5-fold (n=5, p<0.05) as well as prolongs the lag-phase for arrhythmia appearance 4.0+/-0.5-fold (n=5, p<0.01). The lag period for arrhythmia onset was also lengthened (2.0+/-0.4-fold) by NCX(IF) in the ventricle strips (n=6, p<0.002). At low frequency of pacing (1 Hz), all three tested substances, lidocaine, KB-R7943, and NCX(IF) can effectively suppress the ouabain-induced arrhythmia. However, at higher frequency (2 Hz), lidocaine is ineffective in suppressing arrhythmia, whereas KB-R7943 becomes pro-arrhythmic. In contrast to reference drugs, NCX(IF) retains its anti-arrhythmic capacity at high frequencies, either in the atria (n=6, p<0.01) or ventricle (n=5, p<0.05) strips. In conclusion, NCX(IF) results in rapid, effective and stable suppression of arrhythmia both in the atria and ventricle preparations under conditions at which the reference drugs become ineffective.
先前的研究表明，心脏钠钙交换体（NCX1）的纯化内源性抑制剂（NCX(IF)）具有调节心肌收缩力的能力。在此，我们测试了纯化的NCX(IF)对哇巴因诱导的豚鼠心房和心室条带心律失常的影响。为了进行比较，将NCX(IF)与利多卡因和KB-R7943进行了对比。在心室条带中，NCX(IF)（约10 U/ml）可快速、完全且稳定地抑制哇巴因诱导的心律失常（心律失常受到抑制后不会出现不规则收缩的恢复）。在类似的实验条件下，心房条带需要稍高剂量的NCX(IF)（25 - 50 U/ml）才能完全抑制心律失常。在心房条带中，NCX(IF)（10 - 25 U/ml）使哇巴因引发心律失常的阈值剂量（1 microM）增加2.2±0.5倍（n = 5，p < 0.05），并使心律失常出现的延迟期延长4.0±0.5倍（n = 5，p < 0.01）。在心室条带中，NCX(IF)也使心律失常起始的延迟期延长（2.0±0.4倍）（n = 6，p < 0.002）。在低频起搏（1 Hz）时，所有三种受试物质，利多卡因、KB-R7943和NCX(IF)都能有效抑制哇巴因诱导的心律失常。然而，在较高频率（2 Hz）时，利多卡因抑制心律失常无效，而KB-R7943则会促发心律失常。与参比药物不同，NCX(IF)在高频时在心房（n = 6，p < 0.01）或心室（n = 5，p < 0.05）条带中均保持其抗心律失常能力。总之，在参比药物失效的条件下，NCX(IF)能在心房和心室制剂中快速、有效且稳定地抑制心律失常。
