Effect of combination potassium channel blockers on cardiac refractoriness in isolated rabbit hearts and intact guinea pig hearts

grantor: University of TorontoDofetilide and sotalol prolong ventricular refractoriness by blocking the rapidly activating delayed rectifier potassium channel (Ikr). ' In vitro' studies suggest that dofetilide blocks the Ikr channel in the open state, whereas sotalol may block the closed state. We tested whether this potential differential state-dependent blockade could be pharmacologically distinguished by altering Ikl current density. Sotalol (4 [mu]M) and dofetilide (8 nM) were given alone and in combination with 3 [mu]M barium (Ikl blocker) to isolated perfused Langendorff rabbit hearts (n = 8 per group). Ventricular effective refractory period (VERP), action potential duration, ventricular fibrillation cycle length, and defibrillation threshold were measured pre and post drug/vehicle treatment. The VERP was prolonged with dofetilide, sotalol, barium, combination dofetilide plus barium, and sotalol plus barium by 10 ± 6%, 8 ± 2%, 7 ± 3%, 24 ± 5%, and 8 ± 4%, respectively (p < 0.01). The effect of dofetilide plus barium on VERP was additive, whereas sotalol plus barium was no different than each drug alone; this interaction was qualitatively the same for all other variables measured. This is the first study to show that different Ikr blockers have differing effects when combined with another potassium channel blocker.M.Sc