Cardiac electrophysiologic and antiarrhythmic actions of a pavine alkaloid derivative, O-methyl-neocaryachine, in rat heart.
1. O-methyl-neocaryachine (OMNC) suppressed the ischaemia/reperfusion-induced ventricular arrhythmias in Langendorff-perfused rat hearts (EC50=4.3 microM). Its electrophysiological effects on cardiac myocytes and the conduction system in isolated hearts as well as the electromechanical effects on the papillary muscles were examined. 2. In rat papillary muscles, OMNC prolonged the action potential duration (APD) and decreased the maximal rate of depolarization (V(max)). As compared to quinidine, OMNC exerted less effects on both the V(max) and APD but a positive inotropic effect. 3. In the voltage clamp study, OMNC decreased Na+ current (I(Na)) (IC50=0.9 microM) with a negative-shift of the voltage-dependent inactivation and a slowed rate of recovery from inactivation. The voltage dependence of I(Na) activation was, however, unaffected. With repetitive depolarizations, OMNC blocked I(Na) frequency-dependently. OMNC blocked I(Ca) with an IC(50) of 6.6 microM and a maximum inhibition of 40.7%. 4. OMNC inhibited the transient outward K+ current (I(to)) (IC50=9.5 microM) with an acceleration of its rate of inactivation and a slowed rate of recovery from inactivation. However, it produced little change in the steady-state inactivation curve. The steady-state outward K+ current (I(SS)) was inhibited with an IC50 of 8.7 microM. The inward rectifier K+ current (I(K1)) was also reduced by OMNC. 5. In the perfused heart model, OMNC (3 to 30 microM) prolonged the ventricular repolarization time, the spontaneous cycle length and the atrial and ventricular refractory period. The conduction through the AV node and His-Purkinje system, as well as the AV nodal refractory period and Wenckebach cycle length were also prolonged (30 microM). 6. In conclusion, OMNC blocks Na+, I(to) and I(SS) channels and in similar concentrations partly blocks Ca2+ channels. These effects lead to a modification of the electromechanical function and may likely contribute to the termination of ventricular arrhythmias. These results provide an opportunity to develop an effective antiarrhythmic agent with modest positive inotropy as well as low proarrhythmic potential.
Chang
Gwo-Jyh
GJ
Graduate Institute of Clinical Medicine, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
Su
Ming-Jai
MJ
Hung
Li-Man
LM
Lee
Shoei-Sheng
SS
D000200:Action Potentials / Q000187:drug effects; D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000503:physiopathology; D044182:Benzylisoquinolines; D020746:Calcium Channels, L-Type / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000150:complications; D010210:Papillary Muscles / Q000187:drug effects / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects; D051381:Rats; D011921:Rats, Inbred WKY; D015222:Sodium Channels / Q000187:drug effects
D000470:Alkaloids; D000889:Anti-Arrhythmia Agents; D044182:Benzylisoquinolines; D020746:Calcium Channels, L-Type; C467808:O-methylneocaryachine; D015221:Potassium Channels; D015222:Sodium Channels