12 BOTH OPENING AND CLOSING OF GAP JUNCTIONS MAY RESULT IN PROTECTION AGAINST THE ACUTE ISCHAEMIA- INDUCED SEVERE VENTRICULAR ARRHYTHMIAS IN ANAESTHETISED DOGS

after the administration of the IKr blocker, dofetilide, the IKs blocker, HMR-1556, and the IK1 blocker, BaCl2, and their combi-nation, intravenously. Dofetilide significantly increased the QTc interval and induced TdP in 28 % of animals; HMR-1556 or BaCl2 alone had little effect on QTc and did not cause TdP. The combi-nation of dofetilide and HMR-1556, BaCl2 and dofetilide signifi-cantly increased the QTc interval, the QTV and led to a high incidence of TdP (82 % and 63%). In conclusion, the QTV and the incidence of TdP increased markedly following the combined phar-macological block of IKs and IKr as well as after combined block of IK1 and IKr. Our results suggest that QTV may be a better predictor of subsequent TdP development than the prolongation of the QTc interval alone. The current model, where repolarisation reserve is impaired by pharmacological block of one or more potassium currents, may be utilised for more reliable testing of drugs in development for their possible proarrhythmic side effects