Electrophysiological mechanisms for the antiarrhythmic action of (-)-caryachine in rat heart.

Abstract

(-)-Caryachine (CNMe) is a pavine derivative, isolated from Cryptocarya chinensis Hemsl. We wished to illustrate the electrophysiological effect and antiarrhythmic potential of this compound on rat cardiac tissues. Action potential and ionic currents in single ventricular cells were examined by current clamp or voltage clamp in a whole-cell configuration. CNMe concentration-dependently suppressed the maximum rate of rise of the action potential upstroke (V(max)) and prolonged the action potential duration at 50% of repolarization (APD(50)). A voltage-clamp study showed that the suppression of V(max) by CNMe was associated with an inhibition of sodium inward current (I(Na), IC(50), O = 4.1 microM). The prolongation of APD(50) was associated with an inhibition of transient outward current (I(to), IC(50) = 16.1 microM). CNMe reduced the I(Na) with a negative shift of its voltage-dependent steady-state inactivation curves and slowing of its recovery from inactivation. The use-dependent inhibition of I(Na) by CNMe was enhanced at a higher stimulation rate or at a longer prepulse duration. The fraction of fast recovery of I(Na) was reduced, but the recovery time constant of fast recovery component remained unaffected. The inhibition of I(to) by CNMe (10-30 microM) was associated with an acceleration of its time constant of inactivation. According to the analysis of the time course of inhibition of I(to), CNMe inhibited I(to) in a time-dependent manner. In isolated heart, CNMe could effectively inhibit ischemia/reperfusion-induced ventricular tachycardia with an EC(50) of 3.9 microM. The results indicate that CNMe is a strong I(Na) blocker with some I(to) blocking activity. The inhibition of I(Na), and I(to) may contribute to its antiarrhythmic activity against ischemia/reperfusion arrhythmia.