© 2001 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Potassium and calcium current blocking properties of the novel antiarrhythmic agent H 345/52: implications for proarrhythmic potential
aAstraZeneca Research & Development Mölndal, Integrative Pharmacology, S-43183 Mölndal, Sweden
bHPC N.V., Oostende, Belgium
* Corresponding author. Tel.: +46-31-776-1682; fax: +46-31-776-3766 leif.g.carlsson{at}astrazeneca.com
Objectives: To study the blocking effects of H 345/52 on ionic currents of rabbit ventricular myocytes and how these features translate into a proarrhythmic potential. Methods: The single electrode voltage clamp technique was used to study the effects of H 345/52 on the rapid component of the delayed rectifying potassium current, IKr, and the L-type calcium current (ICa). Differential effects of H 345/52 and almokalant on APD prolongation were studied in a rabbit Purkinje fibre/ventricular muscle preparation. The temporal variability of the action potential duration (APD) and its relation to proarrhythmias was examined in Langendorff-perfused rabbit hearts administered H 345/52 or almokalant. Anaesthetised, methoxamine-sensitised rabbits were used to assess the propensity of intravenous H 345/52 and ibutilide to induce torsades de pointes (TdP). Results: H 345/52 potently blocked IKr (IC50=40 nM) without consequential use-dependency. The ICa was also blocked, but at higher concentrations (IC50=1.3 µM). Block of ICa was markedly frequency-dependent (positive) and influenced by membrane potential, such that H 345/52 was more effective following clamp steps from plateau potentials than from –80 mV. In the Purkinje fibre–ventricular muscle preparation, almokalant prolonged the Purkinje fibre APD preferentially, whereas H 345/52 homogeneously prolonged APD in both tissue types. In the perfused rabbit heart, H 345/52 (1 µM) and almokalant (0.3 µM) prolonged APD to a similar degree but increased the temporal variability of APD differently, from 3±0.4 ms in control hearts to 8±1.2 ms and to 38±7.5 ms (P<0.001 vs. H 345/52), respectively. Unequivocal early after-depolarisations were seen in 5/6 almokalant-perfused hearts but in no heart administered H 345/52 (P<0.05). In anaesthetised rabbits, H 345/52 (17.4 µmol/kg) or ibutilide (2.6 µmol/kg maximum), maximally lengthened the QT interval from 133±4.5 to 177±8.0 ms and from 125±5.1 to 166±9.3 ms (P<0.001, n = 8). However, whereas ibutilide induced TdP in all animals at 0.06±0.009 µmol/kg, H 345/52 did not induce TdP (P = 0.0002) at up to 17.4 µmol/kg. Conclusions: H 345/52 blocks IKr with high potency and ICa with somewhat lower potency and was found to delay ventricular repolarisation without substantially increasing temporal or spatial dispersion and without inducing early after-depolarisations or TdP.
KEYWORDS Antiarrhythmic agents; K-channel; Long QT syndrome; QT dispersion; Ventricular arrhythmias
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