Electrophysiological safety of sertindole in dogs with normal and remodeled hearts.

Inhibition of the potassium current IKr and QT prolongation are associated with drug-induced torsades de pointes arrhythmias (TdP) and sudden cardiac death. We investigated the cardiac electrophysiological effects of sertindole, an antipsychotic drug reported to prolong the QT interval in schizophrenic patients. In cell cultures, sertindole seemed to be a selective blocker of IHERG over other ion currents. For IHERG, the IC50 value was 64 +/- 7 nM, whereas ISCN5A, ICa,L, ICa,T, IKCNQ1/KCNE1, and IKv4.3 were blocked in the micromolar range. In canine ventricular myocytes, the IC50 value for IKr inhibition by sertindole was 107 +/- 21 nM. Action potentials in these cells prolonged in a reverse rate- and concentration-dependent manner at 10 to 300 nM sertindole. In vivo, sertindole was administered to anesthetized dogs at clinically relevant (0.05-0.20 mg/kg) and high doses (1.0-2.0 mg/kg) i.v. At 0.05 to 0.20 mg/kg sertindole (plasma concentrations 30-157 nM), QTc was prolonged by 1 to 5% in normal dogs and by 9 to 20% in dogs with remodeled hearts due to chronic atrioventricular block (CAVB). TdP was not induced at these doses in normal dogs or in CAVB dogs with reproducible induction of TdP by dofetilide in previous experiments. At 1.0 to 2.0 mg/kg sertindole (plasma concentrations 0.5-3.1 microM), QTc prolonged by 6 to 11% in normal dogs and by 22% in dofetilide-sensitive CAVB dogs. TdP occurred in three of five animals in the latter group. Thus, at high i.v. doses sertindole can pose a serious proarrhythmic risk when electrical remodeling of the ventricles is present. At clinically relevant doses, however, sertindole does not cause TdP in anesthetized dogs with normal or remodeled hearts.

HTS techniques to investigate the potential effects of compounds on cardiac ion channels at early-stages of drug discovery.

Within the past few years, the high-throughput screening (HTS) of compounds targeting cardiac ion channels has been primarily focused on the testing of the HERG channel, which is involved in the termination of cardiac action potential. Interaction of drugs with this channel may induce QT interval prolongation and cardiac arrhythmia. These undesirable side effects have forced several pharmaceutical companies to terminate drug discovery and development projects. The screening of compounds for HERG-mediated activity early in the drug development process may thus help reduce the number of compounds that are withdrawn from late preclinical or early clinical trials due to cardiovascular side effects. However, early screening implies the ability to test large numbers of compounds. Therefore, tests have to be performed rapidly, combining high-throughput and low costs, and allow the use of small amounts of compounds. In this review, the HTS systems currently available to investigate the potential effects of compounds on the activity of the cardiac HERG ion channel will be described and compared.

Local anaesthetics block hyperpolarization-activated inward current in rat small dorsal root ganglion neurones.

(1) Hyperpolarizing voltage steps evoke slowly activating inward currents in a variety of neurones and in cardiac cells. This hyperpolarization-activated inward current (I(h)) is thought to play a significant role in cell excitability, firing frequency, or in setting of the resting membrane potential in these cells. We studied the effects of lidocaine, mepivacaine, QX-314 and bupivacaine as well as its enantiomers on I(h) in the membrane of dorsal root ganglion neurones (DRG). (2) The patch-clamp technique was applied to small dorsal root ganglion neurones identified in 200 micro M thin slices of young rat DRGs. Under voltage-clamp conditions, the whole-cell I(h) current was recorded in the presence of different concentrations of the local anaesthetics. In current-clamp mode the resting membrane potential and the voltage response of DRG neurones to injected current pulses were investigated. (3) I(h) was reversibly blocked by bupivacaine, lidocaine and mepivacaine applied externally in clinically relevant concentrations. Concentration-response curves gave half-maximum inhibiting concentrations of 55, 99 and 190 micro M, respectively. Bupivacaine block of the I(h) current was not stereoselective. No significant effect was observed when QX-314 was applied to the external surface of the membrane. (4) In current-clamp experiments 60 micro M bupivacaine slightly hyperpolarized the membrane. The membrane stimulation by low-amplitude current pulses in the presence of bupivacaine showed an increase of the hyperpolarizing responses. (5) Our findings suggest an important role of the I(h)-block by local anaesthetics in the complex mechanism of drug action during epidural and spinal anaesthesia.