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 microM, liriodenine was able to convert a polymorphic ventricular tachyrhythmia induced by the ischaemia-reperfusion (EC50 = 0.3 microM). 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 (Vmax) 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 microM) 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 (IC50 = 2.5 microM, maximal inhibition = 35%). 7. Liriodenine inhibited the 4-AP-sensitive transient outward current (Ito) (IC50 = 2.8 microM) 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 microM). 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 IK1, and lesser extent of block on ICa and Ito. 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.
Chang
G J
GJ
Pharmacological Institute, College of Medicine, National Taiwan University, Taipei.
Wu
M H
MH
Wu
Y C
YC
Su
M J
MJ
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D001060:Aporphines / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004594:Electrophysiology; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010946:Plants, Medicinal / Q000737:chemistry*; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism
D000889:Anti-Arrhythmia Agents; D000975:Antioxidants; D001060:Aporphines; D015220:Calcium Channels; D002316:Cardiotonic Agents; D015221:Potassium Channels; D015222:Sodium Channels; C081279:aporphine; C026980:liriodenine