Selective blockade of the inward rectifier potassium channel IK1 by barium, or of the rapidly activating delayed rectifier potassium channel IKr by D,L-sotalol, prolongs repolarization and reduces the defibrillation threshold (DFT). This study hypothesized that combination IK1 and IKr 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 µM), intermediate (3.1 µM), and high (12.5 µM) 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 µM) (p < 0.05), there was no significant additive interaction between barium and D,L-sotalol on VERP or VFCL. Combination IK1 and IKr channel block by barium and D,L-sotalol does not produce additive reduction of DFT.Key words: antiarrhythmic drugs, defibrillation, K+ channel, refractory period, ventricular fibrillation.
GW26-e1386 Mechanism of hERG potassium channel block by tolterodine
