Electrophysiological mechanisms for antiarrhythmic efficacy and positive inotropy of liriodenine, a natural aporphine alkaloid from Fissistigma glaucescens

Gwo Jyh Chang, Mei Hwan Wu, Yang Chang Wu, Ming Jai Su*

*此作品的通信作者

研究成果: 期刊稿件文章同行評審

40 引文 斯高帕斯(Scopus)

摘要

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 μM, liriodenine was able to convert a polymorphic ventricular tachyrhythmia induced by the ischaemia-reperfusion (EC50 = 0.3 μM). 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 (V(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 (IC50 = 0.7 μM) 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 Ca2+ currents (I(Ca)) were also decreased, but to a lesser degree (IC50 = 2.5 μM, maximal inhibition = 35%). 7. Liriodenine inhibited the 4-AP-sensitive transient outward current (I(to)) (IC50 = 2.8 μM) 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)) (IC50 = 1.9 μM). These effects were consistent with its prolonging effect on action potential duration. The inwardly rectifying background K+ current (I(K1)), 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.

原文英語
頁(從 - 到)1571-1583
頁數13
期刊British Journal of Pharmacology
118
發行號7
DOIs
出版狀態已出版 - 1996
對外發佈

指紋

深入研究「Electrophysiological mechanisms for antiarrhythmic efficacy and positive inotropy of liriodenine, a natural aporphine alkaloid from Fissistigma glaucescens」主題。共同形成了獨特的指紋。

引用此