Clinical and Experimental Pharmacology and Physiology (2007) 34, 1313–1316 doi: 10.1111/j.1440-1681.2007.04805.x Blackwell Publishing Asia Original Articles Sevoﬂurane effects in LQT3 model J Kang et al. FUNCTIONAL INTERACTION BETWEEN DPI 201-106, A DRUG THAT MIMICS CONGENITAL LONG QT SYNDROME, AND SEVOFLURANE ON THE GUINEA-PIG CARDIAC ACTION POTENTIAL Jiesheng Kang, Xiao-Liang Chen, William P Reynolds and David Rampe Department of Drug Safety Evaluation, Sanoﬁ-Aventis US Inc., Bridgewater, New Jersey, USA SUMMARY 1. Sevoﬂurane produces QT prolongation on the electro- cardiogram, predominantly via inhibition of the slow delayed rectiﬁer K + current. DPI 201-106 is an experimental drug that produces QT prolongation by reducing Na + channel inactivation, thereby mimicking congenital long QT syndrome type 3 (LQT3). The present study explores the electrophysiological conse- quences of administration of sevoﬂurane in the presence of impaired Na + channel activity. 2. We examined the effects of sevoﬂurane and DPI 201-106, alone and in combination, on the cardiac action potential of guinea-pig ventricular myocytes using standard microelectrode techniques. 3. Both sevoﬂurane and DPI-201-106 prolonged action potential duration, with the combination of the two drugs producing greater than additive effects. Similarly, instability and triangulation of the action potential waveform, measures of pro-arrhythmia, were more pronounced when both drugs were combined. 4. Sevoﬂurane treatment signiﬁcantly alters cardiac action potential waveforms when administered in the presence of impaired Na + channel inactivation. These results indicate the potential for ventricular arrhythmia when sevoﬂurane is administered to LQT3 patients and suggests caution when using sevoﬂurane in this population. Key words: arrhythmia, DPI 201-106, human ether-a-go-go- related gene (HERG), potassium channels, QT prolongation, sevoﬂurane, sodium channels, torsades de pointes. INTRODUCTION Long QT syndrome can be classiﬁed into two types, congenital and acquired. Congenital long QT syndrome refers to a heterogeneous group of inherited disorders that affect cardiac ion channels or their associated proteins. Mutations in these proteins lead to a delay in ventricular repolarization giving rise to a prolongation of the QT interval measured on the surface electrocardiogram (ECG) and pre- dispose carriers to ventricular arrhythmia and sudden cardiac death. 1 Acquired long QT syndrome results when drug administration, often as an unintended side-effect, slows ventricular repolarization, result- ing in QT interval prolongation and the potential to produce ventri- cular arrhythmia such as torsades de pointes. Virtually all cases of acquired long QT syndrome can be traced to a speciﬁc inhibition of the human ether-a-go-go-related gene (HERG) K + channel that carries the rapid delayed rectiﬁer K + current (I Kr ) in the human heart. 2 Many commonly prescribed drugs, including antibiotics, anti- psychotics and antihistamines, are known to be speciﬁc inhibitors of HERG/I Kr and, under certain clinical situations, may increase the risk of ventricular arrhythmia. 3 Sevoﬂurane is a widely used volatile anaesthetic that produces QT interval prolongation in clinical use. 4–6 Unlike other drugs that pro- duce QT prolongation, sevoﬂurane delays ventricular repolarization mainly via an inhibition of the KvLQT1/minK K + channel that carries the slow delayed rectiﬁer current (I Ks ) in the human heart. 7,8 Thus, the mechanism by which sevoﬂurane prolongs cardiac repolarization is somewhat unique among clinically used drugs. DPI 201-106 is an experimental positive inotropic drug that delays cardiac Na + channel inactivation and prolongs the QT interval in humans. 9,10 The mechanism of action of DPI 201-106 on cardiac Na + channels is similar to the inherited defect found in patients with congenital long QT syndrome type (LQT) 3. Indeed, based upon its effects on the human electrocardiogram (ECG) and its ability to promote ventricular arrhythmia, including torsades de pointes, DPI 201-106 is considered a pharmacological mimic of LQT3. 11 We have previously shown that the combination of sevoﬂurane and Class III anti-arrhythmic drugs like sotalol have synergistic effects on action potential prolongation. 8 Although these Class III anti-arrhythmic drugs share one commonality with DPI 201-106 (the ability to delay repolarization and prolong QT interval), they do so by an entirely different mechanism, namely block of HERG/I Kr . In some ways, these Class III anti-arrhythmics may mimic congenital LQT2. Because of these distinct mechanisms of action, the electrophysiological con- sequences of sevoﬂurane administration (producing I Ks inhibition) in the presence of delayed Na + channel inactivation (as would be seen in LQT3) may or may not be similar to those observed previously for Class III anti-arrhythmic drugs. The purpose of the present study was to examine the combination of these two potentially pro-arrhythmic mechanisms on the action potential waveform of guinea-pig ventricular myocytes. METHODS Electrophysiological recordings Single ventricular myocytes from male guinea-pigs were used to record action potentials. Single ventricular myocytes were isolated from guinea-pigs as Correspondence: David Rampe, Sanoﬁ-Aventis, Inc., Route 202-206, Building JR2-2236, Bridgewater, NJ 08807, USA. Email: david.rampe@ sanoﬁ-aventis.com Received 8 May 2007; revision 20 July 2007; accepted 16 August 2007. © 2007 The Authors Journal compilation © 2007 Blackwell Publishing Asia Pty Ltd