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Potassium and calcium current blocking properties of the novel antiarrhythmic agent H 345/52: implications for
G J Amos1, C Abrahamsson, G Duker
1AstraZeneca Research & Development Mölndal, Integrative Pharmacology, S-43183, Mölndal, Sweden.
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, I(Kr), and the L-type calcium current (I(Ca)). 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 I(Kr) (IC(50)=40 nM) without consequential use-dependency. The I(Ca) was also blocked, but at higher concentrations (IC(50)=1.3 microM). Block of I(Ca) 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 microM) and almokalant (0.3 microM) 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 micromol/kg) or ibutilide (2.6 micromol/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 micromol/kg, H 345/52 did not induce TdP (P=0.0002) at up to 17.4 micromol/kg.
Conclusions:
H 345/52 blocks I(Kr) with high potency and I(Ca) 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.
Insights
H 345/52 effectively blocks potassium and calcium currents in rabbit hearts, delaying repolarization without increasing proarrhythmic risks like torsades de pointes.
Area of Science:
- Cardiovascular Pharmacology
- Electrophysiology
- Drug Safety Assessment
Background:
- Investigating novel compounds for cardiac effects is crucial for drug development.
- Understanding drug-induced ionic current block is key to predicting proarrhythmic potential.
Purpose of the Study:
- To evaluate the effects of H 345/52 on cardiac ionic currents.
- To assess the proarrhythmic potential of H 345/52 in rabbit models.
Main Methods:
- Utilized single electrode voltage clamp to study I(Kr) and I(Ca) block.
- Examined action potential duration (APD) and variability in Purkinje fiber/ventricular muscle preparations and Langendorff-perfused hearts.
- Assessed torsades de pointes (TdP) induction in anesthetized rabbits.
Main Results:
- H 345/52 potently blocked I(Kr) (IC50=40 nM) and I(Ca) (IC50=1.3 microM).
- H 345/52 prolonged APD homogeneously without increasing temporal variability or inducing early after-depolarizations.
- Unlike ibutilide, H 345/52 did not induce TdP in vivo.
Conclusions:
- H 345/52 exhibits potent I(Kr) and moderate I(Ca) block.
- H 345/52 delays ventricular repolarization with a low proarrhythmic risk profile.
- H 345/52 demonstrates a favorable safety margin compared to known proarrhythmic drugs.