Background: Grapefruit juice causes significant QT prolongation in healthy volunteers and naringenin has been identified as the most potent human ether-a-go-go-related gene (HERG) channel blocker among several dietary flavonoids. The interaction between naringenin and I(Kr)-blocking antiarrhythmic drugs has not been studied. We evaluated the effect of combining naringenin with I(Kr)-inhibiting antiarrhythmic drugs on cardiac I(Kr).
Methods And Results: I(Kr) current was studied by using HERG expressed in Xenopus oocytes, and the two-electrode voltage clamp technique was employed. Antiarrhythmic drugs (azimilide, amiodarone, dofetilide and quinidine) were tested. Experiments were performed at room temperature. Naringenin blocked HERG current dose dependently with an IC(50) of 173.3 +/- 3.1 microM. Naringenin 100 microM alone inhibited HERG current by 31 +/- 6%, and this inhibitory effect was increased with coadministration of 1 or 10 microM antiarrhythmic drugs. When 100 microM naringenin was added to antiarrhythmic drugs, greater HERG inhibition was demonstrated, compared to the current inhibition caused by antiarrhythmic drugs alone. Addition of naringenin significantly increased current inhibition (p < 0.05).
Conclusions: There is an additive inhibitory effect on HERG current when naringenin is combined with I(Kr)-blocking antiarrhythmic drugs. This additive HERG inhibition could pose an increased risk of arrhythmias by increasing repolarization delay and possible repolarization heterogeneity.
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