947-115 Comparative Effects of D-Sotalol, Quinidine and Amiodarone on Dispersion of Ventricular Repolarization in the Isolated Intact Rabbit Heart

Abstract

It has been hypothesized that antiarrhythmic as well as proarrhythmic effects of antiarrhythmic drugs (AA) can be linked to changes in dispersion of ventricular repolarization (DISP). The influence of d-sotalol (D-SOT). quinidine (QUIN) and amiodarone (AMIO) was studied in isolated Langendorff-perfused rabbit hearts. Between 5–7 monophasic action potentials were recorded simultaneously from both ventricles at steady-state cycle lengths (CL) between 300 and 1200 msec and measured at 90% repolarization (APD 90 ). DISP was defined as APD 90 max - APD 90 min. The protocol was repeated after infusion of D-SOT(n = 12.10 -6 M, 10 -5 M and 5 x 10 -5 M)and QUIN(n = 8, 10 -6 M and 10 -5 M). AMIO was given chronically po. for 4 weeks (n = 9) and compared to n = 18 normal hearts. DISP change compared to the respective baseline (values ranged between 20–27 msec) is shown in the table at selected CLs (all values mean ± SEM in msec, * p < 0.05). AMIO tissue levels correlated with APD duration but not with DISP. CL 300 600 900 1200 D-SOT 10 -6 M +2 ± 3 +5 ± 3 +4±2 +4 ± 3 D-5OT 10 -5 M +11 ± 2 * +14 ± 3 * +10 ± 3 * +11 ± 3 * D-SOT 5 × 10 -5 M +18 ± 2 * +22 ± 3 * +24 ± 3 * +45 ± 10 * OUIN 10 -6 M +14 ± 5 * +22 ± 6 * +18 ± 4 * +28 ± 4 * OUIN 10 -5 M +22 ± 5 * +15 ± 5 * +29 ± 5 * +31 ± 6 * AMIO +3 ± 2 -4 ±2 -3 ± 2 +3 ± 3 Neither of the three drugs with class III-action shows a reduction of DISP. While QUIN and D-SOT show dose-dependent increases in DISP, especially at long CLs, AMIO tissue concentrations are not related to DISP and no increase is seen at long CLs. These effects on DISP may explain the different clinical incidence of torsade de pointes between the three drugs.