Cardiac electrophysiological effects of the new szv-2649, an amiodarone-like mexiletine analogue, and the citrus flavonoid hesperetin in cardiac preparations

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Abstract in foreign language

juices, research has indicated that grapefruit juice can prolong cardiac repolarization in healthy individuals, as evidenced by the QTc interval. Subsequent investigations have validated this finding in healthy participants and individuals with long QT syndrome and cardiomyopathy. Moreover, these studies have highlighted an augmented temporal disparity in cardiac repolarization, as indicated by the short-term variability of the QT interval, suggesting an increased vulnerability to cardiac arrhythmias. Our recent experimental data indicates that hesperetin, a citrus flavonoid, affects potassium channels and lengthens the QTc interval in humans. In dog and rabbit ventricular preparations, hesperetin at 10 μM did not affect the amplitude of IK1, Ito, and IKr potassium currents, but at 30 μM, it decreased these currents in a statistically significant manner. It reduced the amplitude of IKs current in a concentration-dependent manner at 3-30 μM and significantly Abstract 2 decreased the amplitudes of INaL and ICaL currents at 30 μM. Although hesperetin (10 and 30 μM) did not alter the action potential duration in normal preparations, it elicited a moderate but statistically significant prolongation of repolarization in preparations with reduced repolarization reserve induced by 100 nM dofetilide and 1 μg/ml veratrine. These findings indicate that hesperetin inhibits IKs outward potassium current at near-relevant concentrations, reducing repolarization reserve and potentially lengthening the QT interval under specific conditions, thereby increasing the risk of arrhythmia. Together, the studies highlight the potential of SZV-2649 as a safer antiarrhythmic agent compared to amiodarone and underscore the need for caution with hesperetin due to its effects on QT interval prolongation and arrhythmia risk under certain conditions.

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