title: 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.
abstract: 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.
authors.affiliation: 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
authors.forename: Gwo-Jyh
authors.initials: GJ
authors.lastname: Chang
authors.forename: Ming-Jai
authors.initials: MJ
authors.lastname: Su
authors.forename: Sheng-Chu
authors.initials: SC
authors.lastname: Kuo
authors.forename: Tsung-Ping
authors.initials: TP
authors.lastname: Lin
authors.forename: Ying-Shiung
authors.initials: YS
authors.lastname: Lee
mesh_terms: 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
chemical_list: D000889:Anti-Arrhythmia Agents; D020746:Calcium Channels, L-Type; D005663:Furans; D015221:Potassium Channels; D015363:Quinolones; D015222:Sodium Channels; C109999:HA 7