Masaaki Ishii

Canine digitalis arrhythmia as a model for detecting Na-channel blocking antiarrhythmic drugs: A comparative study using other canine arrhythmia models and the new antiarrhythmic drugs, propafenone, tocainide, and SUN 1165

SummaryAntiarrhythmic effects of three new drugs, propafenone, tocainide, and SUN 1165, were examined using three canine ventricular arrhythmia models, i.e., digitalis, adrenaline and two-stage coronary ligation arrhythmias. The effects of procainamide, disopyramide, lidocaine, and phenytoin, class 1 antiarrhythmic drugs, on digitalis arrhythmia were also examined. The minimum effective plasma concentrations of all these drugs for each arrhythmia model were determined for a quantitative comparison. Propafenone and tocainide suppressed all the arrhythmias, while SUN 1165 suppressed digitalis and coronary ligation arrhythmias. The minimum effective plasma concentrations of propafenone for digitalis, adrenaline, 24-h coronary ligation, and 48-h coronary ligation arrhythmias were 1.8±0.7, 0.58±0.20, 3.5±0.3, and 3.6±0.9 µg/ml, respectively, and those of tocainide were 6.2±2.1, 23.7±9.0, 11.4±0.5, and 8.6±2.9 µg/ml, respectively (mean±standard deviation,n=6–7). The minimum effective concentrations of SUN 1165 for digitalis, 24-h coronary ligation, and 48-h coronary ligation arrhythmias were 0.92±0.19, 2.5±0.4, and 1.2±0.4 µg/ml. The minimum effective concentrations for digitalis arrhythmias were 1.7±0.4 µg/ml for disopyramide, 10.1±2.4 µg/ml for procainamide, 3.5±1.6 µg/ml for lidocaine, and 11.3±3.0 µg/ml for phenytoin. Digitalis arrhythmia seems to be a useful model for detecting class 1 drugs, as it was suppressed by all the class 1 Na-channel blocking antiarrhythmic drugs, while class 2 beta adrenergic blockers and class 4 Ca-channel blockers had no effect. Also, not all the class 1 drugs suppressed coronary ligation and adrenaline arrhythmias.

Effective Plasma Concentrations of Aprindine in Canine Ventricular Arrhythmias

Antiarrhythmic effects of aprindine were examined using three canine ventricular arrhythmia models (induced by digitalis, adrenaline, and two-stage coronary ligation), and the minimum effective plasma concentration of aprindine was determined for each arrhythmia model. Aprindine suppressed all three arrhythmias, and the minimum effective plasma concentrations for arrhythmias induced by digitalis, adrenaline, and 24-h and 48-h coronary ligation were 0.8 ± 0.4, 1.0 ± 0.4, 1.6 ± 0.3, and 3.1 ± 0.5 μg/ml, respectively (mean ± SD, n = 6–7). The minimum effective plasma concentrations of aprindine for digitalis- and adrenaline-induced arrhythmias were significantly lower than those for coronary ligation-induced arrhythmias. Oral aprindine was also effective in suppressing both the 24− and 48-h coronary ligation-induced arrhythmias. Aprindine had a hypotensive effect when it was given intravenously, but this effect was not observed when it was given orally. The correlations between the aprindine plasma concentrations and the antiarrhythmic effects were not very strong and indicated individual variations in sensitivity to aprindine.

An electrophysiological comparison of a novel class Ic antiarrhythmic agent, NIK-244 (ethacizin) and flecainide in canine ventricular muscle.

1 Electrophysiological effects of NIK‐244 (ethacizin), a novel class I antiarrhythmic drug, were compared with flecainide in canine ventricular muscle by use of conventional microelectrode techniques. 2 At concentrations of 10−6 m. or higher, NIK‐244 depressed the maximum rate of rise of depolarization () significantly in a concentration‐dependent manner. Also, the resting potential was depolarized at 10−5 m. NIK‐244 did not have any effect on the other action potential parameters or on the effective refractory period. 3 Flecainide significantly decreased at 3 × 10−6 m. or higher and the resting potential was depolarized at 10−5 m. Like NIK‐244, flecainide did not affect other action potential parameters. 4 NIK‐244 and flecainide caused a use‐dependent block of , and the rates of onset of inhibition at 3 Hz stimulation were 0.014 ± 0.002 AP−1 at 2 × 10−6 m. NIK‐244 and 0.021 ± 0.012 AP−1 at 10−5 m. flecainide. Under the same conditions, the time constants of the recovery from use‐dependent block were 27.1 ± 13.3 s and 12.2 ± 2.5 s for NIK‐244 and flecainide, respectively. 5 These results suggest that NIK‐244, like flecainide, should be classified as a slow kinetic drug and as Ic.

Relationships between ventricular arrhythmias and plasma concentrations of ME3202 (CM7857) in dogs.

Two-stage coronary ligation-, digitalis-, and epinephrine (EPI)-induced ventricular arrhythmias were used to establish minimum effective plasma concentrations of ME3202 in dogs. 2-(2-Diisopropylaminoethyl)-4-methyl-2-(2-pyridyl) pentanamide (ME3202) showed antiarrhythmic effects against arrhythmias in all models. The minimum effective plasma concentrations for arrhythmias induced by 24-h coronary ligation, 48-h coronary ligation, digitalis, and EPI were 4.8 ± 1.0 [after 5 mg/kg intravenously (i.v.)], 5.3 ± 1.3 (after 5 mg/kgi.v.), 4.1 ± 1.1 (after 4 mg/kg i.v.), and 2.5 ± 0.8 (after 5 mg/kg i.v.) μg/ml, respectively (mean ± SD, n = 6 or 7). The minimum effective concentration for EPI-induced arrhythmias was significantly lower than those for the other types of arrhythmias. This profile is similar to those of propafenone and nicainoprol, and since ME3202 had no deleterious effects on blood pressure (BP) or sinus node rate, it is expected to be clinically useful.