The in vitro measurement of action potential duration is one test system used for assessing the potential of compounds to cause QT prolongation and torsade de pointes arrhythmias in man. The aim of this study was to compare the effect of compounds known to prolong QT and cause torsade arrhythmias through inhibition of I_Kr/HERG channels on action potential parameters recorded from guinea-pig ventricular myocytes (VM) and dog Purkinje fibres (PF) under the same conditions.

Cardiac PF were removed from the ventricles of dogs killed with an overdose of sodium pentobarbitone. Ventricular myocytes were isolated from hearts removed from guinea-pigs following stunning and cervical dislocation. The dog PF and guinea-pig VM were superfused with physiological salt solution at 36-37 °C containing (mM): NaCl 125; KCl 5.4; CaCl₂ 1.8; MgCl₂ 1.0; NaH₂PO₄ 1.2; NaHCO₃ 25; D-glucose 5.5 (pH 7.4; gassed with 95 % O₂ and 5 % CO₂). Action potentials were stimulated at a frequency of 1 Hz and recorded with microelectrodes containing 3 M KCl (PF) or 1 M KMeSO₄ with 10 mM KCl (VM). Data are means ± S.E.M.

The effect of dofetilide, sparfloxacin, sotalol and cisapride on action potential duration at 90 % repolarisation (APD₉₀) in dog PF and guinea-pig VM is shown in Figs 1 and 2. Dofetilide and sotalol caused a greater prolongation of APD₉₀ in dog PF compared with guinea-pig VM: dofetilide (100 nM) increased APD₉₀ by 56 ± 5 % in dog PF and by 23 ± 1 % in guinea-pig VM and sotalol (100 mM) increased APD₉₀ by 43 ± 9 % in dog PF and by 29 ± 9 % in guinea-pig VM. Sparfloxacin (1-100 mM) prolonged APD₉₀ to a similar extent in both preparations: at 100 mM, APD₉₀ was increased by 31 ± 8 % in dog PF and by 26 ± 4 % in guinea-pig VM. The effect of cisapride on APD₉₀ was biphasic in both preparations with a small prolongation at lower concentrations which was reversed (VM) or converted to a shortening (PF) at higher concentrations. The maximum cisapride-induced prolongation of APD₉₀ occurred at a lower concentration in the guinea-pig VM compared with dog PF. Cisapride and sparfloxacin also reduced the maximum rate of depolarization, indicating an effect on Na channels. This action may have contributed to the biphasic change in APD₉₀ observed with cisapride.

In conclusion, a prolongation of action potential duration was detected with all four compounds in both preparations. This indicates that the guinea-pig VM is likely to be a suitable preparation in which to assess the possible effect of compounds to prolong action potential duration through inhibition of I_Kr/HERG and this preparation may be considered more ethically acceptable for this use than dog cardiac tissue.

All procedures accord with current UK legislation.