ELECTROPHYSIOLOGICAL BASIS FOR ANTIARRHYTHMIC EFFICACY, POSITIVE INOTROPY AND LOW PROARRHYTHMIC POTENTIAL OF (-)-CARYACHINE

1 (-)-Caryachine, isolated from the plant (Cryptocarya chinensis), inc reased the contractility of atrial and right ventricular strips and si gnificantly suppressed the reperfusion arrhythmias in adult rabbit hea rt (ED(50) = 1.27 mu M) 2 Data obtained by the whole-cell voltage clam p technique has shown that (-)-caryachine causes a negative shift of t he 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 mu M (-)-caryachine, re spectively. 3 This agent also had effects on the time- and voltage-dep endent K currents. (-)-Caryachine markedly suppressed the 4-AP-sensiti ve transient outward current (I-to). However, it produced very little voltage-dependent shift in inactivation. After 0.5, 1.5 and 4.5 mu M o f the compound, the respective value of I,, elicited at +60 mV was 80/-7%, 45+/-8% and 15+/-3%. At higher concentrations, the inward rectif ier K current (I-Kl) was also inhibited but to a much smaller extent. Its slope conductance after 0.5, 1.5 and 4.5 mu M (-)-caryachine was r educed to 71+/-9%, 51+/-12% and 42+/-11%, respectively. The outward hu mp of inward rectification was not changed. 4 In contrast, the L-type Ca current was not significantly changed by (-)-caryachine. 5 Electrop hysiological studies in perfused whole heart preparations revealed tha t (-)-caryachine increased the intra-atrial conduction interval and al so prolonged the atrial refractory period. No proarrhythmic effects we re induced during the infusion of this compound (up to 13.5 mu M) 6 We conclude that (-)-caryachine predominantly blocks the Na and I-to cur rents. These changes alter the electrophysiological properties of the heart and terminate the induced ventricular arrhythmias. The relativel y selective I-to inhibition, safety margin of I-Kl suppression and lac k of effect on I-Ca-L will provide an opportunity to develop an effect ive antiarrhythmic agent with positive inotropy as well as low proarrh ythmic potential.