Electrophysiological profile of the antiarrhythmic compound asocainol studied on perfused guinea-pig hearts and on isolated cardiac preparations

The studies deal with electrophysiological effects of asocainol [(±)-6,7,8,9-tetrahydro-2,12-dimethoxy-7-methyl-6-phenetyl-5H-dibenz(d,f)azonine-1-ol] on isolated perfused guinea-pig hearts (Langendorff-preparation), on right ventricular papillary muscles, on Purkinje fibres from the guinea pig, and on isolated sinus nodes from the rabbit. In the perfused heart (n=5) the lowest effective concentration of asocainol is about 0.2 μmol/l. At a concentration of 2 μmol/l the cardiac electrogram shows in spontaneously beating hearts a mean decrease in frequency of 15%, in electrically driven hearts (150/min at 32°C) prolongation of PQ (+31%), of QRS (+24%) and of QT (+5%). In papillary muscles (32° C; K _e ⁺ 5.9 mmol/l; stimulation rate 0.5 Hz) asocainol (3–30 μmol/l) exerts the following effects: no change of the resting potential, concentration-dependent reduction of the maximum rate of rise \(\dot V_{max} \) of the action potential (AP) (−16 to −67%) as well as of the AP-amplitude (−4 to −16%), and shortening of the AP-duration at 50% repolarisation (−18 to −43%). The steady-state dependence of \(\dot V_{max} \) on the resting potential (RP) determined by variation of K _e ⁺ (5.9–15 mmol/l) is shifted by asocainol to more negative potentials. The percentage deviation from controls of the \(\dot V_{max} \) -RP relationship is more pronounced at lower membrane potentials. The influence of asocainol on the recovery from inactivation of \(\dot V_{max} \) shows marked time-dependence. Slow response (Ca²⁺-mediated) APs elicited by strong stimuli in a K _e ⁺ -rich solution (K _e ⁺ 20–24 mmol/l) respond to asocainol (3–10 μmol/l) with a marked reduction in amplitude, \(\dot V_{max} \) and duration. In Purkinje fibres the spontaneous activity occurring in K _e ⁺ 2 mmol/l (37°C) is suppressed by asocainol (3–10 μmol/l). The excitatory parameters are affected in a way essentially similar to that in papillary muscles. In the primary pacemaker region of the sinus node of the rabbit (37°C) asocainol (10–20 μmol/l) reduces the rate of the diastolic depolarisation and diminishes the amplitude and the upstroke velocity of the AP. All the effects of asocainol are only partially reversible by drug-free superfusion for 3 h. The various electrophysiological effects of asocainol are attributed to inhibitory influences of the drug on the fast and on the slow inward current.