title: Class III antiarrhythmic effects of LY-190147 on defibrillation threshold.
abstract: Defibrillation strength shocks delivered within an action potential (AP) delay repolarization. Shock-induced AP duration extension (APDE) may prolong refractoriness and terminate or prevent reinitiation of reentry, favoring defibrillation. This study examined LY-190147 (LY) effects on defibrillation threshold (DFT) in 11 dogs. Ventricular effective refractory period (VERP) and epicardial monophasic AP duration at 75% repolarization (APD75) were recorded at 300-, 400-, 500-, and 600-ms pacing cycle length (CL). APDE was measured as the time to 50% repolarization after a DFT strength shock delivered at 50, 25, and 0 ms before or 25 ms after VERP during pacing at 300 ms CL in 4 of the dogs. We made all recordings before drug administration and after infusions of 0.03, 0.3, and 3.0 mg/kg LY, using 1.5-h dosing intervals. LY lowered DFT in a saturating dose-response manner whether expressed as shock peak voltage (V) or energy. LY decreased DFT-V from 357 +/- 77 V before drug to 331 +/- 60 V (-6 +/- 12%), 290 +/- 43 V (-17 +/- 13%, p < 0.001), and 312 +/- 45 V (-11 +/- 12%, p < 0.05) at 0.03, 0.3, and 3.0 mg/kg, respectively. Similarly, LY treatment decreased defibrillation energy requirements from 6.9 +/- 2.7 J before drug by 7 +/- 25%, 26 +/- 24%, and 12 +/- 25% at the same doses. At 300-600 ms CL, LY prolonged APD75 by an average of 10 +/- 8% at 0.03 mg/kg, 17 +/- 6% at 0.3 mg/kg, and 24 +/- 9% at 3 mg/kg. At these CL, LY prolonged VERP by an average of 4 +/- 6% at 0.03 mg/kg, 15 +/- 10% at 0.3 mg/kg, and 11 +/- 9% at 3 mg/kg. APDE was increased from 62 +/- 9 ms before to 68 +/- 14, 80 +/- 16 (p < 0.001) and 72 +/- 13 ms (p < 0.05) at 0.03, 0.3, and 3.0 mg/kg LY, respectively. Therefore, LY prolonged VERP and APDE and affected DFT in the same saturating dose-response manner. LY may facilitate defibrillation by increasing the duration of postshock refractoriness.
authors.affiliation: University of Ottawa Heart Institute, Faculty of Medicine, Canada.
authors.forename: G N
authors.initials: GN
authors.lastname: Beatch
authors.forename: D R
authors.initials: DR
authors.lastname: Dickenson
authors.forename: R H
authors.initials: RH
authors.lastname: Wood
authors.forename: A S
authors.initials: AS
authors.lastname: Tang
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D017147:Defibrillators, Implantable; D004285:Dogs; D015507:Drugs, Investigational / Q000494:pharmacology*; D004554:Electric Countershock
chemical_list: D000889:Anti-Arrhythmia Agents; D015507:Drugs, Investigational