title: Combination IK1 and IKr channel blockade: no additive lowering of the defibrillation threshold.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of Toronto, ON, Canada.
authors.forename: Pryamvada
authors.initials: P
authors.lastname: Varma
authors.forename: Xiangqian
authors.initials: X
authors.lastname: Qi
authors.forename: David
authors.initials: D
authors.lastname: Newman
authors.forename: Paul
authors.initials: P
authors.lastname: Dorian
mesh_terms: D000465:Algorithms; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001464:Barium / Q000494:pharmacology; D051668:Delayed Rectifier Potassium Channels; D004305:Dose-Response Relationship, Drug; D004554:Electric Countershock; D004594:Electrophysiology; D006334:Heart Function Tests; D066298:In Vitro Techniques; D008297:Male; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors*; D024642:Potassium Channels, Voltage-Gated; D011817:Rabbits; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D013015:Sotalol / Q000494:pharmacology
chemical_list: D000889:Anti-Arrhythmia Agents; D051668:Delayed Rectifier Potassium Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D024642:Potassium Channels, Voltage-Gated; D001464:Barium; D013015:Sotalol