Effects of purified endogenous inhibitor of the Na⁺/Ca²⁺ exchanger on ouabain-induced arrhythmias in the atria and ventricle strips of guinea pig

Previous studies demonstrated that the purified endogenous inhibitor (NCX_IF) of the cardiac Na⁺/Ca²⁺ 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 (∼ 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 μM) 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.