QT PRODACT: Evaluation of the Potential of Compounds to Cause QT Interval Prolongation by Action Potential Assays Using Guinea-Pig Papillary Muscles

Abstract

Certain compounds that prolong QT interval in humans have little or no effect on action-potential (AP) duration used traditionally, but they inhibit rapidly-activated-delayed-rectifier potassium currents (IKr) and/or human ether-a-go-go-related gene (hERG) currents. In this study using isolated guinea-pig papillary muscles, we investigated whether new parameters in AP assays can detect the inhibitory effects of various compounds on IKr and/or hERG currents with high sensitivity. The difference in AP duration between 60% and 30% repolarization, 90% and 60% repolarization, and 90% and 30% repolarization (APD30–60, APD60–90, and APD30–90, respectively) were calculated as the new parameters. All the 15 IKr and/or hERG current inhibitors that have been reported (9 compounds) or not reported (6 compounds) to inhibit calcium currents prolonged APD30–60, APD60–90, and/or APD30–90; and 8 of the 15 inhibitors prolonged APD30–60, APD60–90, and/or APD30–90 more potently than APD90. The APD30–60, APD60–90, and APD30–90 measurements revealed no difference in sensitivity when evaluating the effects of the IKr and/or hERG current inhibitors on the three parameters. On the other hand, compounds with little or no effect on hERG currents had no effect on APD30–60, APD60–90, or APD30–90. Therefore, it is concluded that in AP assays using isolated guinea-pig papillary muscles, APD30–60, APD60–90, and APD30–90 are useful indexes for evaluating the inhibitory effects of compounds including mixed ion-channel blockers on IKr and/or hERG currents.Supplementary material (Appendix): available only at http://dx.doi.org/10.1254/jphs.QT-C8