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

Abstract

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 gM, liriodenine was able to convert a polymorphic ventricular tachyrhythmia induced by the ischaemiareperfusion (EC50 = 0.3 gM).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 (7,,ma) 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 (INa) concentration-dependently (IC50 = 0.7 gM) 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 (ICa) were also decreased, but to a lesser degree (ICo = 2.5 gM, maximal inhibition = 35%). 7 Liriodenine inhibited the 4-AP-sensitive transient outward current (I,.) (IC50 = 2.8 gM) and moderately accelerated its rate of decay. The block of Ito 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 (ISS) (IC50 = 1.9 ,M). These effects were consistent with its prolonging effect on action potential duration. The inwardly rectifying background K+ current (IK1), was also decreased but to a less degree. 8 Compared to quinidine, liriodenine exerted a stronger degree of block on INa, comparable degree of block on IKi, and lesser extent of block on ICa and In,. 9 It is concluded that, through inhibition of Na+ and the Ito channel, liriodenine can suppress ventricular arrhythmias induced by myocardial ischaemia reperfusion. The positive inotropic effect can be explained by inhibition of the Ito channel and the subsequent prolongation of action potential duration. These results provide a satisfactory therapeutic potential for the treatment of cardiac arrhythmias.

Ionic Mechanisms for the Antiarrhythmic Action of Cinnamophilin in Rat Heart

“…These results suggest that Cinn may exert antiarrhythmic activity by a mode of action similar to class I, III and IV antiarrhythmic agents. The potency of antiarrhythmic activity is comparable to some natural alkaloids such as (-)-caryachine [43] but weaker than N-allylsecoboldine [41] and liriodenine [6].…”

Review on pharmacological activities of liriodenine

“…This alkaloid was isolated for the first time from Liriodendron tulipifera L., and was subsequently isolated from plant species of many genera (Warthen et al, 1969), mainly found in the families of Magnoliaceae, Annonaceae, Rutaceae, Monimiaceae, and Menispermaceae (Bentley, 2001;Hsieh et al, 2005;Lan et al, 2003;Lin et al, 1994;Nissanka et al, 2001;Woo et al, 1997;Wu et al, 1990). This has a wide range of pharmacological activities, such as activity against Grampositive bacteria (Camacho et al, 2000;Li et al, 2009;Mohamed et al, 2010;Rahman et al, 2005;Waechter et al, 1999), antifungal (Hufford et al, 1980;Khan et al, 2002), antitumoral (Chen et al, 2009Liu et al, 2009), antiarrhythmic activity (Chang et al, 1996(Chang et al, , 2001Chung et al, 2004), antiviral activities (Mohamed et al, 2010) and antiplatelet actions (Chen et al, 1997;Pyo et al, 2003). The objective of this work was to compile information about liriodenine, which may help researcher to understand the efficacy and potency of this alkaloid.…”

“…The in vivo biological studies indicated that through inhibition of the Na + and I to channels, liriodenine suppresses antiarrhythmic activity induced by myocardial ischaemia reperfusion (Chang et al, 1996). An increased concentration of NO limits myocardial ischemia-reperfusion injury.…”

Historic Perspectives on Annonaceous Acetogenins from the Chemical Bench to Preclinical Trials

“…and Goniothalamus amuyon (Blanco) Merr., are native to the Taiwan island [28,29]. Our early studies on the Formosan Annonaceous plants focused on alkaloids, which showed diverse biological functions, including cytotoxicity [30], antiplatelet aggregation activity [31], cardiovascular activity [32,33] and antimicrobial activity [34]. Afterwards, diterpenoids, styrylpyrones [12,35,36] and some linear AGEs [37], mono-THF AGEs [38,39], and adjacent bis-THF AGEs [39] were isolated from various parts of the Annona plants in our laboratory.…”

“…Because substantial amounts of pure samples are required for further biological and clinical studies, a number of total syntheses of AGEs have been reported in the literature since the 1990s. Recent advances in the total syntheses of AGEs include mono-THF AGEs: murisolin (26) [90,91], longicin (27) [92,93], and cis-solamin (28) [94,95], adjacent bis-THF AGEs: bullatacin (14) [96], rolliniastatin 1 (7) [23,97], rollimembrin (29) [97,98], 10-hydroxyasimicin (30) [99,100], membranacin (31) [97,101], asimicin (15) [76,102], longimicin D (32) [103][104], and mucoxin (33) [105,106], non-adjacent bis-THF AGEs: cis-sylvaticin (34) [107,108] and gigantecin (9) [109,110], and others, jimenezin (35) [111,112], mucocin (36) [113,114], pyranicin (37) [115,116], pyragonicin (38) [115,117,118], rollicosin (18) [62,…”