Effects of a new antiarrhythmic compound [2-benzal-1-(2' diisopropyl-amino-ethoxy-imino)-cycloheptane hydrogen fumarate] on the electrophysiological properties of mammalian cardiac cells.

Intracellular microelectrodes were used to study the effects of Th 494 [2-benzal-1-(2' diisopropyl-amino-ethoxy-imino)-cycloheptane hydrogen fumarate; 1-100 mumol/1) on transmembrane electrical activity of sinus node and Purkinje fibres of the rabbit as well as on atrial trabeculae and papillary muscles of the guinea pig. In the atrial and in the ventricular myocardium (32 degrees C; driving rate 0.3-0.5 Hz) Th 494 exerted the following electrophysiological actions: no change of the resting potential nor of the amplitude of the action potential; concentration- dependent reduction of the maximum rate of rise (dV/dt)max of the action potential; slight increase of the action potential duration at lower concentrations (1-20 mumol/l), loss of the plateau at higher concentrations (above 20 mumol/l). The isometric force of contraction was moderately reduced by Th 494 (about 20% reduction by 2 mumol/l). The h infinity-curve relating (dV/dt)max of the action potential to the membrane potential was depressed by Th 494 without being shifted along the voltage axis. The reduction of (dV/dt)max was considerably more pronounced at higher driving frequencies. After interruption of stimulation for various periods, (dV/dt) max of the first action potential attained a steady-state value in a two-exponential fashion, suggesting use-dependence as well as a change in the recovery kinetics of the fast Na+ channel by Th 494. In Purkinje fibres (37 degrees C) Th 494 reduced (dV/dt) max in a similar manner. The duration of the action potential was considerably decreased at the level of the plateau. In the primary pacemaker region of the sinus node (37 degrees C) Th 494 moderately reduced the rate of diastolic depolarization and diminished at higher concentrations the amplitude of the action potential. All effects of Th 494 were only slowly reversible by drug-free perfusion. In view of its effect on (dV/dt) max, Th 494 resembles quinidine in its potential-dependence, whereas its time-dependence bears greater similarity with lidocaine.