Claudia Kiesecker

QTc Prolongation by Grapefruit Juice and Its Potential Pharmacological Basis HERG Channel Blockade by Flavonoids

Background—A high intake of dietary flavonoids, which are abundant in fruits, vegetables, tea, and wine, is known to reduce cardiovascular mortality. The effects of flavonoids on cardiac electrophysiology, which theoretically may have both antiarrhythmic and proarrhythmic consequences, have not been studied systematically to date. Methods and Results—We screened a broad spectrum of flavonoids for their inhibitory activity on HERG channels by using heterologous expression in Xenopus oocytes. At a concentration of 1 mmol/L, 10 compounds caused a significant inhibition of HERG currents, whereas 11 other flavonoids had no effect. The IC50 value for HERG block by naringenin, the most potent inhibitor, was 102.3 &mgr;mol/L in Xenopus oocytes and 36.5 &mgr;mol/L in HEK cells. To demonstrate the physiological relevance of these findings, we studied the effects of pink grapefruit juice, which contains large amounts of naringenin glycosides (>1000 &mgr;mol/L), in human volunteers. In 10 persons, we observed a peak QTc prolongation of 12.5±4.2 ms 5 hours after oral ingestion of 1 L of grapefruit juice. This effect was significant (P=0.02). Conclusions—We found a significant QTc prolongation by grapefruit juice in healthy volunteers, probably caused by block of HERG channels by flavonoids. These findings reveal new perspectives on the potential for dietary modification of cardiac electrophysiology.

Regulation of two-pore-domain (K2P) potassium leak channels by the tyrosine kinase inhibitor genistein

Two‐pore‐domain potassium (K2P) channels mediate potassium background (or ‘leak’) currents, controlling excitability by stabilizing membrane potential below firing threshold and expediting repolarization. Inhibition of K2P currents permits membrane potential depolarization and excitation. As expected for key regulators of excitability, leak channels are under tight control from a plethora of stimuli. Recently, signalling via protein tyrosine kinases (TKs) has been implicated in ion channel modulation. The objective of this study was to investigate TK regulation of K2P channels.

Regulation of cardiac inwardly rectifying potassium current Ik1 and Kir2.x channels by endothelin-1

To elucidate the ionic mechanism of endothelin-1 (ET-1)-induced focal ventricular tachyarrhythmias, the regulation of IK1 and its main molecular correlates, Kir2.1, Kir2.2 and Kir2.3 channels, by ET-1 was investigated. Native IK1 in human atrial cardiomyocytes was studied with whole-cell patch clamp. Human endothelin receptors were coexpressed with human Kir2.1, Kir2.2 and Kir2.3 channels in Xenopus oocytes. Currents were measured with a two-microelectrode voltage clamp. In human cardiomyocytes, ET-1 induced a marked inhibition of IK1 that could be suppressed by the protein kinase C (PKC) inhibitor staurosporine. To investigate the molecular mechanisms underlying this regulation, we studied the coupling of ETA receptors to homomeric and heteromeric Kir2.1, Kir2.2 and Kir2.3 channels in the Xenopus oocyte expression system. ETA receptors coupled functionally to Kir2.2 and Kir2.3 channels but not to Kir2.1 channels. In Kir2.2 channels lacking functional PKC phosphorylation sites, the inhibitory effect was abolished. The inhibition of Kir2.3 currents could be suppressed by the PKC inhibitors staurosporine and chelerythrine. The coupling of ETA receptors to heteromeric Kir2.1/Kir2.2 and Kir2.2/Kir2.3 channels resulted in a strong inhibition of currents comparable with the effect observed in Kir2.2 homomers. Surprisingly, in heteromeric Kir2.1/Kir2.3 channels, no effect was observed. ET-1 inhibits human cardiac IK1 current via a PKC-mediated phosphorylation of Kir2.2 channel subunits and additional regulatory effects on Kir2.3 channels. This mechanism may contribute to the intrinsic arrhythmogenic potential of ET-1.

807-2 Selective inhibition of human cardiac Kir2.2 inward rectifier channels by adrenergic alpha-1a receptors

Ca rd ia c Ar rh yt hm ia s (N588K) in the pore forming region of the cardiac Kr channel (KCNH2, HERG). The mutations dramatically increase IKr leading to heterogeneous abbreviation of action potential duration and refractoriness and rendering the channel relatively unresponsive to IKr blockers. Conclusion: Our data point to a novel genetic mechanism responsible for sudden death in children, infants and young adults. The mutation leads to a heterogeneous abbreviation of action potential duration and refractoriness, creating the substrate for reentrant arrhythmias.