Comparison of the proarrhythmic effects of combined Ikr and Iks blockade in anaesthetized rabbits and guinea pigs

Georghia Michael, Kathleen A Kane & Susan J Coker, Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, Glasgow, G4 0NR, UK

Torsade de pointes is a life-threatening arrhythmia associated with long QT (LQT) syndromes, which can be induced by blockade of the main cardiac repolarizing currents, IKs (LQT1) and I Kr (LQT2). Previously, we have shown in an anaesthetized rabbit model that the IKs blocker HMR1556 did not cause torsade de pointes when given alone but significantly potentiated the torsadogenic action of the IKr blocker E-4031 (Michael et al., 2006). As guinea pigs have more IKs than rabbits (Lu et al., 2001) it is possible that IKs block will have greater effects in the guinea pig. The aim of this study was therefore to compare the effects of HMR1556 (Gerlach et al., 2001) alone and in combination with E-4031 (Sanguinetti & Jurkiewicz, 1990) in both species.Experiments were performed in pentobarbital-anaesthetised α1-adrenoceptor-stimulated male New Zealand White rabbits (2.2 – 2.8 kg) and male Dunkin-Hartley guinea pigs (320 – 520 g). Rabbits received three consecutive i.v. infusion rates of either E-4031 (1, 3 and 10 nmol kg-1 min-1, n = 8), HMR1556 (25, 75 and 250 nmol kg-1 min-1, n = 7) or E-4031 and HMR1556 combined (doses as above, n = 8). Three guinea pigs received E-4031 combined with HMR1556 at the doses stated above and three further guinea pigs received 3-fold higher doses of both drugs. The effects of HMR1556 (250 nmol kg-1 min-1) alone were also examined in guinea pigs. Fisher’s exact tests were used to compare arrhythmia incidences and Kruskal-Wallis tests were used for arrhythmia duration. Differences were considered statistically significant when P<0.05.
Torsade de pointes occurred in 25% of rabbits given E-4031 and in 75% of rabbits receiving the combination, but not in rabbits treated with HMR1556 alone. A significantly greater duration of torsade de pointes was observed in the combination group (261 ± 65 s) compared with E-4031 alone (10 ± 9 s). No torsade de pointes occurred in guinea pigs receiving HMR1556 alone, or the combination given at the same doses as in the rabbits, or at the higher doses. Other arrhythmias including ventricular tachycardia and ventricular premature beats were observed in all rabbits in the first cycle of drug infusion. Only a few ventricular premature beats were observed in some of the guinea pigs. Conduction disturbances were observed in 88% of rabbits and 100% of guinea pigs receiving the combination treatment, and no significant differences were observed in the total duration of conduction block between species (rabbit: 1664 ± 64 s; guinea pig: 1004 ± 418 s).

The present findings indicate that the α1-adrenoceptor-stimulated anaesthetized rabbit model is more susceptible to torsade de pointes than guinea pigs following combined blockade of I Ks and I Kr . In addition, conduction block does not appear to be a contributory factor in the development of torsade de pointes.

Gerlach U. et al., (2001) J. Med. Chem. 44 : 3831-3837.
Lu Z. et al., (2001) Circulation 104 : 951-956.
Michael G. et al., (2006) J. Mol. Cell. Cardiol. 40 : 985.
Sanguinetti M.C. & Jurkiewicz N.K. (1990) J. Gen. Physiol. 96 : 195-215.

This work was supported by the British Heart Foundation (FS/03/118).