ELECTROPHYSIOLOGICAL MECHANISMS FOR ANTIARRHYTHMIC EFFICACY AND POSITIVE INOTROPY OF LIRIODENINE, A NATURAL APORPHINE ALKALOID FROM FISSISTIGMA-GLAUCESCENS
Gj. Chang et al., ELECTROPHYSIOLOGICAL MECHANISMS FOR ANTIARRHYTHMIC EFFICACY AND POSITIVE INOTROPY OF LIRIODENINE, A NATURAL APORPHINE ALKALOID FROM FISSISTIGMA-GLAUCESCENS, British Journal of Pharmacology, 118(7), 1996, pp. 1571-1583
1 The antiarrhythmic potential and electromechanical effects of liriod
enine, an aporphine alkaloid isolated from the plant, Fissistigma glau
cescens, were examined. 2 In the Langendorff perfused (with constant p
ressure) rat heart, at a concentration of 0.3 to 3 mu M, liriodenine w
as able to convert a polymorphic ventricular tachyrhythmia induced by
the ischaemia-reperfusion (EC(50) = 0.3 mu M). 3 In isolated atrial an
d 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 outwa
rd K+ channel blocker, 4-aminopyridine (4-AP) but was not significantl
y 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 depola
rization (V-max) and resting membrane potential in a concentration-dep
endent manner. The action potential amplitude was not significantly ch
anged. 6 Whole-cell voltage clamp study revealed that liriodenine bloc
ked the Na+ channel (I-Na) concentration-dependently (IC50=0.7 mu M) a
nd caused a leftward shift of its steady-state inactivation curve. How
ever, its recovery rate from the inactivated state was not affected. T
he L-type Ca2+ currents (I-Ca) were also decreased, but to a lesser de
gree (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) an
d 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 inacti
vating, steady-state outward. current (I-ss) (IC50=1.9 mu M). These ef
fects were consistent with its prolonging effect on action potential d
uration. The inwardly rectifying background K+ current (I-K1), was als
o decreased but to a less degree. 8 Compared to quinidine, liriodenine
exerted a stronger degree of block on I-Na, comparable degree of bloc
k on I-K1 and lesser extent of block on I-Ca and I-to. 9 It is conclud
ed that, through inhibition of Na+ and the I-to channel, liriodenine c
an suppress ventricular arrhythmias induced by myocardial ischaemia re
perfusion. The positive inotropic effect can be explained by inhibitio
n of the I-to channel and the subsequent prolongation of action potent
ial duration. These results provide a satisfactory therapeutic potenti
al for the treatment of cardiac arrhythmias.