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Electrophysiological mechanisms for antiarrhythmic efficacy and positive inotropy of liriodenine, a natural aporphine alkaloid from Fissistigma glaucescens
Author(s) -
Chang GwoJyh,
Wu MeiHwan,
Wu YangChang,
Su MingJai
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15577.x
Subject(s) - aporphine , alkaloid , electrophysiology , tian , pharmacology , chemistry , medicine , neuroscience , biology , stereochemistry , art , literature
1 . The antiarrhythmic potential and electromechanical effects of liriodenine, an aporphine alkaloid isolated from the plant, Fissistigma glaucescens , were examined. 2 . In the Langendorff perfused (with constant pressure) rat heart, at a concentration of 0.3 to 3 μ m , liriodenine was able to convert a polymorphic ventricular tachyrhythmia induced by the ischaemia‐reperfusion (EC 50 = 0.3 μ m ). 3 . In isolated atrial and ventricular muscle, liriodenine increased the contractile force and slowed the spontaneous beating of the right atrium. 4 . The liriodenine‐induced positive inotropy was markedly attenuated by a transient outward K + channel blocker, 4‐aminopyridine (4‐AP) but was not significantly affected by prazosin, propranolol, verapamil or carbachol. 5 . In rat isolated ventricular myocytes, liriodenine prolonged action potential duration and decreased the maximal upstroke velocity of phase 0 depolarization (V̇ max ) and resting membrane potential in a concentration‐dependent manner. The action potential amplitude was not significantly changed. 6 . Whole‐cell voltage clamp study revealed that liriodenine blocked the Na + channel ( I Na ) concentration‐dependently (IC 50 = 0.7 μ m ) and caused a leftward shift of its steady‐state inactivation curve. However, its recovery rate from the inactivated state was not affected. The L‐type Ca 2+ currents ( I Ca ) were also decreased, but to a lesser degree (IC 50 = 2.5 μ m , maximal inhibition = 35%). 7 . Liriodenine inhibited the 4‐AP‐sensitive transient outward current ( I to ) (IC 50 = 2.8 μ m ) and moderately accelerated its rate of decay. The block of I to was not associated with changes in the voltage‐dependence of the steady‐state inactivation curve or in the process of recovery from inactivation of the current. Liriodenine also reduced the amplitude of a slowly inactivating, steady‐state outward current ( I ss ) (IC 50 = 1.9 μ m ). These effects were consistent with its prolonging effect on action potential duration. The inwardly rectifying background K + current ( I K***1 ), was also decreased but to a less degree. 8 . Compared to quinidine, liriodenine exerted a stronger degree of block on I Na , comparable degree of block on I K1 , and lesser extent of block on I Ca and I to . 9 . It is concluded that, through inhibition of Na + and the I to channel, liriodenine can suppress ventricular arrhythmias induced by myocardial ischaemia reperfusion. The positive inotropic effect can be explained by inhibition of the I to channel and the subsequent prolongation of action potential duration. These results provide a satisfactory therapeutic potential for the treatment of cardiac arrhythmias.