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Electrophysiological characteristics of antiarrhythmic potential of acrophyllidine, a furoquinoline alkaloid isolated from Acronychia halophylla
Author(s) -
Chang GwoJyh,
Wu MeiHwan,
Chen WenPin,
Kuo ShengChu,
Su MingJai
Publication year - 2000
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/1098-2299(200006)50:2<170::aid-ddr7>3.0.co;2-w
Subject(s) - repolarization , electrophysiology , depolarization , chemistry , ventricle , purkinje fibers , alkaloid , steady state (chemistry) , medicine , refractory period , time constant , membrane potential , ic50 , biophysics , biology , stereochemistry , in vitro , biochemistry , electrical engineering , engineering
The antiarrhythmic potential of acrophyllidine, a natural furoquinoline alkaloid 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 ischemia/reperfusion‐induced polymorphic ventricular tachyarrhythmias with an EC 50 value of 4.4 μM. In the perfused whole‐heart model (constant flow), acrophyllidine increased the atrioventricular and His‐Purkinje system conduction intervals, ventricular repolarization time (VRT), and basic cycle length and also prolonged the refractory periods of the AV node, His‐Purkinje system and ventricle. In isolated rat ventricular myocytes, acrophyllidine prolonged 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 (IC 50 = 3.6 μM) with a negative‐shift of its voltage‐dependent steady‐state inactivation curve and slowing of its recovery from inactivation. Similarly, Ca 2+ inward current (I Ca ) was inhibited but to a lesser extent. Acrophyllidine also suppressed the transient outward (I to ) (IC 50 equals; 4.5 μM) and the steady‐state outward K + current (I SS ) (IC 50 = 3.4 μM). The inhibition of I to was associated with an acceleration of its rate of inactivation. Additionally, acrophyllidine suppressed I to in a time‐dependent manner and caused a negative‐shift of the steady‐state inactivation curve and a slowed rate of recovery from inactivation. It is concluded that acrophyllidine blocks Na +, I to and I SS channels and in similar concentrations partly blocks Ca 2+ channel. These changes alter the electrophysiological properties of the conduction system and may be responsible for the termination of the ischaemia/reperfusion induced ventricular arrhythmias. Drug Dev. Res. 50:170–185, 2000. © 2000 Wiley‐Liss, Inc.