Combination IK1 and IKr channel blockade: no additive lowering of the defibrillation threshold

Selective blockade of the inward rectifier potassium channel I(K1) by barium, or of the rapidly activating delayed rectifier potassium channel I(Kr) by D,L-sotalol, prolongs repolarization and reduces the defibrillation threshold (DFT). This study hypothesized that combination I(K1) and I(Kr) channel block would produce concentration-dependent additive effects on DFT and ventricular refractoriness. A range of barium and D,L-sotalol concentrations, alone and in combination, were examined with respect to DFT, ventricular effective refractory period (VERP), and ventricular fibrillation cycle length (VFCL) in 133 Langendorff-perfused rabbit hearts. Barium produced a concentration-dependent reduction of DFT (-49+/-4%), with concentration-dependent increases in VERP (26+/-6%) and VFCL (42+/-18%). D,L-Sotalol produced a concentration-dependent lowering of DFT (-53+/-6%) with a concentration-dependent increase in VFCL (34+/-8%) but not VERP. Low (1.6 microM), intermediate (3.1 microM), and high (12.5 microM) barium concentrations combined with varying D,L-sotalol concentrations produced equal or smaller decreases in DFT compared with corresponding doses of barium or D,L-sotalol alone. Except at the lowest concentrations of barium (1.6 and 3.1 microM) (p < 0.05), there was no significant additive interaction between barium and D,L-sotalol on VERP or VFCL. Combination I(K1) and I(Kr) channel block by barium and D,L-sotalol does not produce additive reduction of DFT.