Electrophysiological basis for antiarrhythmic efficacy, positive inotropy and low proarrhythmic potential of (-)-caryachine.

1. (-)-Caryachine, isolated from the plant (Cryptocarya chinensis), increased the contractility of atrial and right ventricular strips and significantly suppressed the reperfusion arrhythmias in adult rabbit heart (ED50 = 1.27 microM). 2. Data obtained by the whole-cell voltage clamp technique has shown that (-)-caryachine causes a negative shift of the steady-state Na channel inactivation and a slower rate of recovery from inactivation. The maximal Na current amplitude decreased to 67 +/- 7%, 29 +/- 8% and 12 +/- 5% after 0.5, 1.5 and 4.5 microM (-)-caryachine, respectively. 3. This agent also had effects on the time- and voltage-dependent K currents. (-)-Caryachine markedly suppressed the 4-AP-sensitive transient outward current (I10). However, it produced very little voltage-dependent shift in inactivation. After 0.5, 1.5 and 4.5 microM of the compound, the respective value of I10 elicited at +60 mV was 80 +/- 7%, 45 +/- 8% and 15 +/- 3%. At higher concentrations, the inward rectifier K current (IK1) was also inhibited but to a much smaller extent. Its slope conductance after 0.5, 1.5 and 4.5 microM (-)-caryachine was reduced to 71 +/- 9%, 51 +/- 12% and 42 +/- 11%, respectively. The outward hump of inward rectification was not changed. 4. In contrast, the L-type Ca current was not significantly changed by (-)-caryachine. 5. Electrophysiological studies in perfused whole heart preparations revealed that (-)-caryachine increased the intra-atrial conduction interval and also prolonged the atrial refractory period. No proarrhythmic effects were induced during the infusion of this compound (up to 13.5 microM). 6. We conclude that (-)-caryachine predominantly blocks the Na and I10 currents. These changes alter the electrophysiological properties of the heart and terminate the induced ventricular arrhythmias. The relatively selective I10 inhibition, safety margin of Ik1 suppression and lack of effect on Ica-L will provide an opportunity to develop an effective antiarrhythmic agent with positive inotropy as well as low proarrhythmic potential.