Class III Antiarrhythmic Effects of LY-190147 on Defibrillation Threshold

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.