Study Of The Proarrhythmic Potential Of A Promising Detoxification Agents Ibogaine And Its Analogs

ObjectIbogaine has been used to treat series of drug addiction for a long time,however,the side effects has also been recognized and studied including unexplained sudden death syndrome which thought to be caused by malignant ventricular arrhythmia.In this article,some methods,such as the arterially perfused rabbit left ventricular wedge preparation,Western-blot and test on Ca²⁺handling,were used to evaluate the proarrhythmic potential and the underling electrophysiological mechanism of Ibogaine and its analogs including Noribogaine and 18-MC.MethodsFirstly,a rabbit ventricular myocardial wedge model was used to detect the action potential duration,QT interval and ventricular arrhythmias before and after using Ibogaine and its analogs,Noribogaine and 18-MC.All three drugs were performed with four different concentrations.We also test the drugs under hypokalemia conditions.Secondly,the trafficking of hERG channel was investigated in H9C2 cells.The expression of the“mature”and“immature”hERG channel was identified by Western-blot.Thirdly,we also investigated the acute effects of Ibogaine and its analogs on Ca²⁺handling in freshly isolated ventricular myocytes.Results?a?Ibogaine and Noribogaine,all significantly increased the QT interval,T_p-e and APD₉₀ from epicardium and endocardium,18-MC did not prolong the QT interval,T_p-e and APD₉₀ with lower concentrations.As to the occurrence of ventricular arrhythmias,none was recorded with ibogaine perfusion at physiological condition,two propagating TdPs with Noribogaine were recorded with the concentration of 10?M,and three propagating TdP with 25?M.There were also ventricular tachycardias recorded in 18-MC groups at the concentration of 25?M.In contrast to physiological condition,moderate hypokalemic solution perfusion,the occurrence of TdP events all increased.?b?As for the hERG trafficking,the Western-blot demonstrated that the mature and immature hERG protein remained unchanged after exposed to Ibogaine,Noribogaine and 18-MC for 24 hours.?c?The acute effects of Ibogaine and its analogs on Ca²⁺handling decreased amplitudes and prolonged time to peak of Ca²⁺transients in isolated ventricular myocytes.Significant increased spontaneous Ca²⁺release events were detected in treated cells.ConclusionIbogaine and Noribogaine all significantly increased the QT interval and APD₉₀,and Noribogaine had the proarrhythmic effect at 10?M and 25?M.18-MC had little influence on QT interval and APD₉₀,and did not lead to arrhythmia and at therapeutic concentration.As to TdP,hypokalemia presence increased the proarrhythmic risk potential of Ibogaine and its analogs.And both ibogaine and its analogs had no effect on hERG trafficking.Ibogaine and its analogs rapidly increases spontaneous Ca²⁺release and disturbed the Ca²⁺handling in isolated ventricular cells,which might be one of the mechanism of their proarrhythmic effect.