Lack of Clinically Important hERG Channel Block by the Antipsychotics Tiapride and Sulpiride

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 in the delayed rectifier K+ current of guinea pig cardiomyocytes. The amplitude of the hERG outward currents measured at the end of the pulse showed no concentration-dependent change with increasing either tiapride or sulpiride concentration (3-300 μM). Also, the amplitude of hERG tail currents did not show concentration-dependent changes with increasing either tiapride or sulpiride concentration (3-300 μM). However, our findings showed that tiapride increased the values of the potential for half-maximal activation (V1/2) at 10 - 300 μM, on the contrary, sulpiride increased the maximum conductance (Gmax) at 3, 10, 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, but tiapride and sulpiride at the concentrations did not significantly block slowly activating delayed rectifier K+ current (IKs). Our findings suggest that the concentrations of the antipsychotics required to evoke a 50% inhibition of the IKr were well above reported therapeutic plasma concentrations of free and total compound. None of tiapride and sulpiride was a potent blocker of the hERG channel.