Verapamil modulating arsenic trioxide-induced QT interval prolongation in guinea pig

摘要

Objective To investigate therapeutic action of verapamil on QT prolongation induced by arsenic trioxide (As2O3) in guinea pig and to further explore its possible mechanism. Methods Different doses of As2O3 was infused intravenously to observe the changes of QT interval on the electrocardiogram (ECG) at different times in guinea pig.Patch clamp technique and laser scanning confocal microscopy were utilized to study the action of As2O3 on action potential duration (APD),L-type calcium current (ICa-L), rapid delayed rectifier potassium current (IKr) and intracellular calcium concentration ([Ca2+]i) of guinea pig myocytes. At the same time, verapamil was applied preliminarily to evaluate effects of verapamil on changes of the above index induced by AS2O3 . Results Intravenous administration of As2O3 at the dose of 1.6mg/kg and 0.8mg/kg prolonged QT interval on ECG obviously in guinea pig hearts dose dependently and time de pendently. QTc (corrected QT interval) was progressively prolonged in the 2-hour period of intravenous infusion of 1.6mg/ kg As2O3 from (328 .5±30.9)ms of control to (388 .4±31. 3)ms at 2h following As2O3 (P 0 .05) in guinea pig cardiomyoeytes,however, 10μmol/L As2O3 could markedly enhance [Ca2+ ]. increase induced by KCl 60mmol/ L and the peak value increased from 903 .4±369.4 to 1674. 6±563 .2 ( P < 0.05 ) . The action of elevating [ Ca2+ ]i could be blocked by 10μmol/L verapamil incompletely. The patch-clamp studies indicated that As2O3 at concentration of 10μmol/L prolonged APD50 from (263 .6±75 .2)ms to (523.9±47 .8)ms (P<0.01) and APD90 from (277.5±77.5) ms to (536.3±49.6)ms (P<0.01),and increased ICa-L from ( -6.0±1.5)pA/pF to ( -8.7±2.0)pA/pF (P < 0.01) at 0mV and also reduced IKr from (6.7±1.8)pA/pF to (4.5±1 .8)pA/pF ( P < 0.05) .However,10μmol/L verapamil could modulate prolonging APD50 from (523 . 9±47 . 8 ) ms to (340.4±83 . 8 ) ms ( P < 0.01) and APD90 from (536.3±49.6) ms to (348.9±85.5)ms (P < 0.01) and correct increasing ICa-L induced by 10μmol/L As2O3 from ( - 8 .7±2.0) pA/pF to ( - 6.6±1.4) pA/pF ( P < 0.05) at 0mV. Conclusion As2O3 could induce prolongation of the QT interval on the ECG in guinea pig hearts and the ionic mechanism is associated with increasing ICa-L and inhibiting IKr/HERG. Verapamil may be useful in normalizing QT prolongation during As2O3 therapy by decreasing ICa-L and [Ca2+]i of ventricular myocytes in guinea pig.