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

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 mu M, liriodenine was able to convert a polymorphic ventricular tachyrhythmia induced by the ischaemia-reperfusion (EC(50) = 0.3 mu 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 (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 mu 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 Ca2+ currents (I-Ca) were also decreased, but to a lesser degree (IC50=2 5 mu M, maximal inhibition=35%). 7 Liriodenine inhibited the 4-AP-sensitive transient outward current (I-to) (IC50=2.8 mu 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) (IC50=1.9 mu M). 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.