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Abstract. To construct a non-clinical database for drug-induced QT interval prolongation, the electrophysiological effects of 11 positive and 10 negative compounds on action potentials (AP) in guinea-pig papillary muscles were investigated in a multi-site study according to a standard protocol. Compounds with a selective inhibitory effect on the rapidly activated delayed rectifier potassium current (I Kr ) prolonged action potential duration at 90% repolarization (APD 90 ) in a concentration-dependent manner, those showing Ca 2+ current (I Ca ) inhibition shortened APD 30 , and those showing Na + current (I Na ) inhibition decreased action potential amplitude (APA) and V max . Some of the mixed ion-channel blockers showed a bell-shaped concentration-response curve for APD 90 , probably due to their blockade of I Na and / or I Ca , sometimes leading to a falsenegative result in the assay. In contrast, all positive compounds except for terfenadine and all negative compounds with I Kr -blocking activity prolonged APD 30-90 regardless of their I Na -and / or I Ca -blocking activities, suggesting that APD 30-90 is a useful parameter for evaluating the I Krblocking activity of test compounds. Furthermore, the assay is highly informative regarding the modulation of cardiac ion channels by test compounds. Therefore, when APD 90 and APD 30-90 are both measured, the action potential assay can be considered a useful method for assessing the risk of QT interval prolongation in humans in non-clinical safety pharmacology studies. Supplementary material (Appendix): available only at http://dx

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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-delayedrectifier potassium currents (I Kr ) 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 I Kr 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 (APD 30-60 , APD 60-90 , and APD 30-90 , respectively) were calculated as the new parameters. All the 15 I Kr and / or hERG current inhibitors that have been reported (9 compounds) or not reported (6 compounds) to inhibit calcium currents prolonged APD 30-60 , APD 60-90 , and / or APD 30-90 ; and 8 of the 15 inhibitors prolonged APD 30-60 , APD 60-90 , and / or APD 30-90 more potently than APD 90 . The APD 30-60 , APD 60-90 , and APD 30-90 measurements revealed no difference in sensitivity when evaluating the effects of the I Kr 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 APD 30-60 , APD . Therefore, it is concluded that in AP assays using isolated guinea-pig papillary muscles, APD 30-60 , APD 60-90 , and APD 30-90 are useful indexes for evaluating the inhibitory effects of compounds including mixed ion-channel blockers on I Kr and / or hERG currents. Supplementary material (Appendix): available only at http://dx

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