Electrophysiological characteristics of antiarrhythmic potential of acrophyllidine, a furoquinoline alkaloid isolated from Acronychia halophylla

The antiarrhythmic potential of acrophyllidine, a natural furoquinoline alk aloid isolated from the plant, Acronychia halophylla, has been documented. In the present study, the electrophysiological effects of acrophyllidine in Langendorff-perfused rat hearts and isolated cardiomyocytes were examined. In isolated rat heart (constant pressure), acrophyllidine suppressed ische mia/reperfusion-induced polymorphic ventricular tachyarrhythmias with an EC 50 value of 4.4 mu M. In the perfused whole-heart model (constant flow), ac rophyllidine increased the atrioventricular and His-Purkinje system conduct ion intervals, ventricular repolarization time (VRT), and basic cycle lengt h and also prolonged the refractory periods of the AV node, His-Purkinje sy stem and ventricle. In isolated rat ventricular myocytes, acrophyllidine pr olonged the action potential duration (APD) and decreased both the maximal upstroke velocity of depolarization (V-max) and action potential amplitude in a concentration-dependent manner. Whole-cell voltage clamp studies show that acrophyllidine blocked the Na+ channel (IC50 = 3.6 mu M) With a negati ve-shift of its voltage-dependent steady-state inactivation curve and slowi ng of its recovery from inactivation. Similarly, Ca2+ inward current (I-Ca) was inhibited but to a lesser extent. Acrophyllidine also suppressed the t ransient outward (I-to) (IC50 equals; 4.5 mu M) and the steady-state outwar d K+ current (I-SS) (IC50 = 3.4 mu M) The inhibition of I-to was associated with an acceleration of its rate of inactivation. Additionally, acrophylli dine suppressed It, in a time-dependent manner and caused a negative-shift of the steady-state inactivation curve and a slowed rate of recovery from i nactivation. It is concluded that acrophyllidine blocks Na-+,Na- I-to and I -SS channels and in similar concentrations partly blocks Ca2+ channel. Thes e changes alter the electrophysiological properties of the conduction syste m and may be responsible for the termination of the ischaemia/reperfusion i nduced ventricular arrhythmias. (C) 2000 Wiley-Liss, Inc.