Inhibition of Human ether-a-go-go-Related Gene K+ Channel and IKr of Guinea Pig Cardiomyocytes by Antipsychotic Drug Trifluoperazine

Choi, Se‐Young; Koh, Young‐Sang; Jo, Su‐Hyun

doi:10.1124/jpet.104.080853

Cited by 31 publications

(16 citation statements)

References 28 publications

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“…The concentration of chlorpheniramine at the cell membrane may be decreased by the vitelline membrane and egg yolk. The block of hERG by trifluoperazine (Choi et al, 2005) resulted in IC50 values 10 times higher when the drug was applied to Xenopus oocytes rather than to mammalian cells. Therefore, the putative IC50 value for the block of hERG channels by chlorpheniramine in mammalian cells such as human embryonic kidney (HEK) and cardiomyocytes might be in the range of ∼2 μM.…”

Section: Discussionmentioning

confidence: 99%

Block of hERG K+ Channel by Classic Histamine H1 Receptor Antagonist Chlorpheniramine

Hong

2009

Korean J Physiol Pharmacol

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Chlorpheniramine is a potent first-generation histamine H1 receptor antagonist that can increase action potential duration and induce QT prolongation in several animal models. Since block of cardiac human ether-a-go-go-related gene (hERG) channels is one of leading causes of acquired long QT syndrome, we investigated the acute effects of chlorpheniramine on hERG channels to determine the electrophysiological basis for its proarrhythmic potential. W e examined the effects of chlorpheniramine on the hERG channels expressed in Xenopus oocytes using two-microelectrode voltage-clamp techniques. Chlorpheniramine induced a concentration-dependent decrease of the current amplitude at the end of the voltage steps and hERG tail currents. The IC50 of chlorpheniramine-dependent hERG block in Xenopus oocytes decreased progressively relative to the degree of depolarization. Chlorpheniramine affected the channels in the activated and inactivated states but not in the closed states. The S6 domain mutations Y652A and F656A partially attenuated (Y652A) or abolished (F656A) the hERG current block. These results suggest that the H1 antihistamine, chlorpheniramine is a blocker of the hERG channels, providing a molecular mechanism for the drug-induced arrhythmogenic side effects.

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Section: Discussionmentioning

confidence: 99%

Block of hERG K+ Channel by Classic Histamine H1 Receptor Antagonist Chlorpheniramine

Hong

2009

Korean J Physiol Pharmacol

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“…The IC 50 values of many hERG channel blockers have been shown to differ depending on whether the hERG channels are expressed in Xenopus oocytes or mammalian cells, an effect that is probably due to the sequestration of blockers in the large ooplasm of the oocytes [12] . We therefore tested the effect of hydroxyzine on hERG channels expressed in HEK293 cells at 36 °C ( Figure 4).…”

Section: Hydroxyzine Blocks Wt Herg Currents In Hek Cellsmentioning

confidence: 99%

“…Single ventricular myocytes were isolated from guinea pig hearts using a method that was described previously [12] . In brief, guinea pigs (300-500 g) were anesthetized with pentobarbital (~50 mg/kg, ip) and the heart was quickly excised.…”

Section: Ventricular Myocyte Isolationmentioning

confidence: 99%

Effects of the histamine H1 receptor antagonist hydroxyzine on hERG K+ channels and cardiac action potential duration

Lee

Chu

et al. 2011

Acta Pharmacol Sin

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Aim: To investigate the effects of hydroxyzine on human ether-a-go-go-related gene (hERG) channels to determine the electrolphysiological basis for its proarrhythmic effects. Methods: hERG channels were expressed in Xenopus oocytes and HEK293 cells, and the effects of hydroxyzine on the channels were examined using two-microelectrode voltage-clamp and patch-clamp techniques, respectively. The effects of hydroxyzine on action potential duration were examined in guinea pig ventricular myocytes using current clamp. Results: Hydroxyzine (0.2 and 2 μmol/L) significantly increased the action potential duration at 90% repolarization (APD 90 ) in both concentration-and time-dependent manners. Hydroxyzine (0.03-3 μmol/L) blocked both the steady-state and tail hERG currents. The block was voltage-dependent, and the values of IC 50 for blocking the steady-state and tail currents at +20 mV was 0.18±0.02 μmol/L and 0.16±0.01 μmol/L, respectively, in HEK293 cells. Hydroxyzine (5 μmol/L) affected both the activated and the inactivated states of the channels, but not the closed state. The S6 domain mutation Y652A attenuated the blocking of hERG current by ~6-fold. Conclusion:The results suggest that hydroxyzine could block hERG channels and prolong APD. The tyrosine at position 652 in the channel may be responsible for the proarrhythmic effects of hydroxyzine.

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“…Single ventricular myocytes were isolated from each guinea-pig heart using a method described previously (20). Guinea pigs (300 -500 g) were anesthetized with pentobarbital (up to 50 mg/kg, i.p.)…”

Section: Ventricular Myocyte Isolationmentioning

confidence: 99%

Effect of Azelastine on Cardiac Repolarization of Guinea-Pig Cardiomyocytes, hERG K+ Channel, and Human L-type and T-type Ca2+ Channel

et al. 2013

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Abstract. Azelastine is a second generation histamine H 1 -receptor antagonist used as an antiasthmatic and anti-allergic drug that can induce QT prolongation and torsades de pointes. We investigated the acute effects of azelastine on human ether-a-go-go-related gene (hERG) channels, action potential duration (APD), and L-type (I Ca,L ) and T-type Ca 2+ current (I Ca,T ) to determine the electrophysiological basis for its proarrhythmic potential. Azelastine increased the APD at 90% of repolarization concentration dependently, with an IC 50 of 1.08 nM in guinea-pig ventricular myocytes. We examined the effects of azelastine on the hERG channels expressed in Xenopus oocytes and HEK293 cells using two-microelectrode voltage-clamp and patch-clamp techniques. Azelastine induced a concentration-dependent decrease of the hERG current amplitude at the end of the voltage steps and tail currents. The IC 50 for the azelastine-induced block of the hERG currents expressed in HEK293 cells was 11.43 nM, while the drug inhibited I Ca,L and I Ca,T with IC 50 values of 7.60 and 26.21 mM, respectively. The S6 domain mutations, Y652A partially attenuated and F656A abolished hERG current block. These results suggest that azelastine is a potent blocker of hERG channels rather than I Ca,L or I Ca,T , providing molecular mechanisms for the arrhythmogenic side effects during the clinical administration of azelastine.

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Inhibition of Human ether-a-go-go-Related Gene K⁺ Channel and I_Kr of Guinea Pig Cardiomyocytes by Antipsychotic Drug Trifluoperazine

Cited by 31 publications

References 28 publications

Block of hERG K+ Channel by Classic Histamine H1 Receptor Antagonist Chlorpheniramine

Block of hERG K+ Channel by Classic Histamine H1 Receptor Antagonist Chlorpheniramine

Effects of the histamine H1 receptor antagonist hydroxyzine on hERG K+ channels and cardiac action potential duration

Effect of Azelastine on Cardiac Repolarization of Guinea-Pig Cardiomyocytes, hERG K+ Channel, and Human L-type and T-type Ca2+ Channel

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