kjpp The Korean Journal of Physiology & Pharmacology Korean J Physiol Pharmacol 1226-4512 2093-3827 Korean J Physiol Pharmacol 10.4196/kjpp.2010.14.5.305 kjpp-14-305 Original Article Response of IKr and hERG Currents to the Antipsychotics Tiapride and Sulpiride JoSu-Hyun 1 LeeSo-Young 2 Department of Physiology, Institute of Bioscience and Biotechnology, Kangwon National University School of Medicine, Chuncheon 200-701, Korea Department of Life Science, Pohang University of Science and Technology, Pohang 790-784, Korea Corresponding to: Su-Hyun Jo, Department of Physiology, Kangwon National University School of Medicine, Hyoja-dong, Chuncheon 200-701, Korea. (Tel) 82-33-250-8824, (Fax) 82-33-255-8809, (E-mail) suhyunjo@kangwon.ac.kr 022010 18022010 14 5 305 310 19082010 07092010 14092010 Copyright © 2010 Korean J Physiol Pharmacol 2010 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract

The human ether-a-go-go-related gene (hERG) channel is important for repolarization in human myocardium and is a common target for drugs that prolong the QT interval. We studied the effects of two antipsychotics, tiapride and sulpiride, on hERG channels expressed in Xenopus oocytes and also on delayed rectifier K+ currents in guinea pig cardiomyocytes. Neither the amplitude of the hERG outward currents measured at the end of the voltage pulse, nor the amplitude of hERG tail currents, showed any concentration-dependent changes with either tiapride or sulpiride (3∼300 μM). However, our findings did show that tiapride increased the potential for half-maximal activation (V1/2) of HERG at 10 ∼ 300 μM, whereas sulpiride increased the maximum conductance (Gmax) at 3, 10 and 100 μM. In guinea pig ventricular myocytes, bath applications of 100 and 500 μM tiapride at 36°C blocked rapidly activating delayed rectifier K+ current (IKr) by 40.3% and 70.0%, respectively. Also, sulpiride at 100 and 500 μM blocked IKr by 38.9% and 76.5%, respectively. However, neither tiapride nor sulpiride significantly affected the slowly activating delayed rectifier K+ current (IKs) at the same concentrations. Our findings suggest that the concentrations of the antipsychotics required to evoke a 50% inhibition of IKr are well above the reported therapeutic plasma concentrations of free and total compound.

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The effect of tiapride on humanether-a-go-go-related gene (hERG) currents (IHERG) elicited by depolarizing voltage pulses. (A) Superimposed current traces elicited by depolarizing voltage pulses (4 s) in 10 mV steps (upper panel) from a holding potential of –70 mV in the absence of tiapride (control, center panel) and in the presence of 300 μM tiapride (lower panel). (B) Plot of the normalized hERG current measured at the end of depolarizing pulses (IHERG) against the pulse potential in the control and tiapride conditions. The maximal amplitude of the IHERG in the control was given a value of 1. (C) Plot of the normalized tail current measured at its peak just after repolarization. The peak amplitude of the tail current in the absence of the drug was set as 1. Control data were fitted to the Boltzmann Equation, y=1/{1+exp [(–V+V1/2)/dx]}, with V1/2 of –20.8 mV. (D) Plot of the values of V1/2 (open squares) and Gmax (closed circles) against the concentration of tiapride. Symbols with error bars represent mean±S.E.M. (n=3). ∗p<0.05.

The effect of sulpiride on humanether-a-go-go-related gene (hERG) currents (IHERG) elicited by depolarizing voltage pulses. (A) Superimposed current traces elicited by depolarizing voltage pulses (4 s) in 10 mV steps (upper panel) from a holding potential of –70 mV in the absence of sulpiride (control, center panel) and in the presence of 300 μM sulpiride (lower panel). (B) Plot of the normalized hERG current measured at the end of depolarizing pulses (IHERG) against the pulse potential in the control and tiapride conditions. The maximal amplitude of the IHERG in the control was given a value of 1. (C) Plot of the normalized tail current measured at its peak just after repolarization. The peak amplitude of the tail current in the absence of the drug was set as 1. Control data were fitted to the Boltzmann Equation, y=1/{1+exp[(-V+V1/2)/dx]}, with V1/2 of –25.6 mV. (D) Plot of the values of V1/2 (open squares) and Gmax (closed circles) against the concentration of sulpiride. Symbols with error bars represent mean±S.E.M. (n=4). ∗p<0.05.

The effect of tiapride on both slow and rapid components of delayed rectifier K+ currents in guinea pig ventricular myocytes. (A) Representative traces of the rapid component (IKr) and the slow component (IKs) of delayed rectifier K+ channel tail currents before and after treatment with either 100 μM or 500 μM tiapride. (B) A summary of the effects of 100 μM and 500 μM tiapride and 2 μM E-4031 on IKr and IKs tail currents, normalized relative to the control current (n=2∼4, ∗p<0.05). The tail current amplitudes were measured as the difference between the peak outward current and the steady-state current at the end of the repolarizing voltage pulses.

The effect of sulpiride on both slow and rapid components of delayed rectifier K+ currents in guinea pig ventricular myocytes. (A) Representative traces of the rapid component (IKr) and the slow component (IKs) of delayed rectifier K+ channel tail currents before and after treatment with either 100 μM or 500 μM sulpiride. (B) A summary of the effects of 100 μM and 500 μM sulpiride and 2 μM E-4031 on IKr and IKs tail currents, normalized relative to the control current (n=3∼4, ∗p<0.05). The tail current amplitudes were measured as the difference between the peak outward current and the steady-state current at the end of the repolarizing voltage pulses.