Multiple cellular electrophysiological effects of a novel antiarrhythmic furoquinoline derivative HA-7 [N-benzyl-7-methoxy-2,3,4,9-tetrahydrofuro[2,3-b]quinoline-3,4-dione] in guinea pig cardiac preparations.
We studied the electrophysiological and antiarrhythmic actions of HA-7 [N-benzyl-7-methoxy-2,3,4,9-tetrahydrofuro[2,3-b]quinoline-3,4-dione], a furoquinoline alkaloid derivative, in guinea pig heart preparations. In the perfused whole heart model, HA-7 caused a prolongation in the basic cycle length, ventricular repolarization time, and the atrioventricular (AV) nodal Wenckebach cycle length and prolonged the refractory period of the atrium, AV node, and His-Purkinje system. The atrioventricular conduction interval was also prolonged in a frequency-dependent manner. In isolated hearts, HA-7 significantly raised the threshold for experimental atrial fibrillation and reduced the occurrence of reperfusion-induced ventricular fibrillation. Conventional microelectrode-recording study shows that HA-7, but not d-sotalol, prolonged the action potential duration (APD) and decreased the maximum rate of depolarization in isolated atrial strips. In ventricular papillary muscles, higher concentrations of HA-7 caused a prolongation of APD(90) in a frequency-independent manner, whereas d-sotalol exerted a reverse frequency-dependent action on this parameter. Whole-cell patch clamp results on ventricular myocytes indicate that HA-7 decreased both the slow (I(Ks)) (IC(50) = 4.8 muM) and fast component (I(Kr)) (IC(50) = 1.1 muM) of the delayed rectifier K(+) currents. Similar results could also be observed in atrial myocytes. The inward rectifier K(+) current (I(K1)) was also reduced somewhat by HA-7. HA-7 also suppressed the Na(+) inward current (I(Na)) (IC(50) = 2.9 muM) and inhibited the L-type Ca(2+) current (I(Ca)) (IC(50) = 4.0 muM, maximal inhibition = 69%) to a lesser extent. We conclude that HA-7 blocks multiple ionic currents and that these changes affect the electrophysiological properties of the conduction system as well as the myocardial tissues and may contribute to its antiarrhythmic efficacy.
Chang
Gwo-Jyh
GJ
Graduate Institute of Clinical Medicinal Sciences, College of Medicine, Chang Gung University, 5 Fu-Shing St, Kwei-Shan, Tao-Yuan, Taiwan. gjchang@adm.cgmh.org.tw
Su
Ming-Jai
MJ
Kuo
Sheng-Chu
SC
Lin
Tsung-Ping
TP
Lee
Ying-Shiung
YS
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001281:Atrial Fibrillation / Q000188:drug therapy / Q000503:physiopathology; D020746:Calcium Channels, L-Type / Q000187:drug effects; D004562:Electrocardiography / Q000187:drug effects; D004576:Electromyography; D004594:Electrophysiology; D005663:Furans / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006325:Heart Atria / Q000187:drug effects; D006329:Heart Conduction System / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology; D010210:Papillary Muscles / Q000187:drug effects; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism
D000889:Anti-Arrhythmia Agents; D020746:Calcium Channels, L-Type; D005663:Furans; D015221:Potassium Channels; D015363:Quinolones; D015222:Sodium Channels; C109999:HA 7