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 false-negative 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
Kr-blocking 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.doi.org/10.1254/jphs.QT-A1
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