Assessment of proarrhythmic activity of chloroquine in in vivo and ex vivo rabbit models

Abstract

Objectives: To evaluate the prolongation of ventricular repolarization and proarrhythmic activity of antimalarial drug chloroquine in two rabbit proarrhythmia models viz., in vivo α1 adrenoceptor-stimulated anesthetized rabbit and ex vivo isolated Langendorff rabbit heart using clofilium as standard proarrhythmic agent.

Materials and methods: In the in vivo model, three groups of rabbits, anesthetized by pentobarbitone sodium and α-chloralose, sensitized with α1 agonist methoxamine followed by either continuous infusion of saline (control) or clofilium (3 mg/kg) or chloroquine (21 mg/kg) for 30 min. In ex vivo model, rabbit hearts were perfused with clofilium (10 μM) or chloroquine (300 μM) continuously after priming along with methoxamine, acetylcholine chloride and propranolol hydrochloride.

Results: In these models, prolongation of repolarization during α1-adrenoceptor stimulation produced early after depolarization (EAD) and Torsade de pointes (TdP). Saline infusion did not induce any abnormality in the animals. Clofilium caused expected changes in the electrocardiogram in both the models including TdP (50.0% in in vivo and 66.67% in ex vivo). Chloroquine caused decrease in heart rate and increase in the corrected QT (QTc) interval in both the models. Further, apart from different stages of arrhythmia, TdP was evident in 33.33% in ex vivo model, whereas no TdP was observed in in vivo model.

Conclusions: The results indicated that proarrhythmic potential of chloroquine and clofilium was well evaluated in both the models; moreover, both the models can be used to assess the proarrhythmic potential of the new drug candidates.

Keywords: chloroquine; clofilium; ex vivo rabbit model; in vivo rabbit model; torsade de pointes; α1 -Adrenoceptor stimulation.

Figure 1

Incidences of arrhythmia in rabbit in-vivo model where clofilium treated animals showed PVC, II AV Block, VT and TdP while chloroquine treated animals showed PVC, I AV block, II AV Block and VF. (a) Normal sinus rhythm. (b) Atrioventricular (AV) block.(c) Premature ventricular contractions. (d) Ventricular tachycardia (e) Torsade De Pointes (TdP). (f) Ventricular Fibrillation (VF)

Figure 2

Incidences of arrhythmia in rabbit ex vivo model where clofilium and chloroquine treated animals showed PVC, II and III AV Block, VT and TdP (a) Normal sinus rhythm. (b) Premature ventricular contractions. (c) Ventricular tachycardia (VT). (d) 2^rnd Degree Atrioventricular (AV) block. (e) 3^rd Degree Atrioventricular (AV) block. (f) Torsade De Pointes (TdP)