Response of IKr and hERG Currents to the Antipsychotics Tiapride and Sulpiride

초록

The human ether-a-go-go-related gene (hERG) channel is important for repolarizatton 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 similar to 300 mu M) However, our findings did show that tiapride increased the potential for half-maximal activation (V-1/2) of HERG at 10 similar to 300 mu M, whereas sulpiride increased the maximum conductance (G(max)) at 3, 10 and 100 mu M In guinea pig ventricular myocytes, bath applications of 100 and 500 mu M tiapride at 36 degrees C blocked rapidly activating delayed rectifier K+ current (I-Kr) by 40 3% and 70 0%, respectively Also, sulpiride at 100 and 500 mu M blocked I-Kr by 38 9% and 76 5%, respectively However, neither tiapride nor sulpiride significantly affected the slowly activating delayed rectifier K+ current (I-Ks) at the same concentrations Our findings suggest that the concentrations of the antipsychotics required to evoke a 50% inhibition of I-Kr are well above the reported therapeutic plasma concentrations of free and total compound

키워드