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CARDIOVASCULAR

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

Graduate Institute of Clinical Medicinal Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan (G.-J.C., Y.-S.L.); Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan (M.-J.S.); Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan (S.-C.K., T.-P.L.); and the First Cardiovascular Division of Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan (Y.-S.L.)

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 APD₉₀ 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) (IC₅₀ = 4.8 µM) and fast component (I_Kr) (IC₅₀ = 1.1 µM) 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) (IC₅₀ = 2.9 µM) and inhibited the L-type Ca²⁺ current (I_Ca) (IC₅₀ = 4.0 µM, 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.

Address correspondence to: Dr. Gwo-Jyh Chang, Graduate Institute of Clinical Medicinal Sciences, College of Medicine, Chang Gung University, 5 Fu-Shing St, Kwei-Shan, Tao-Yuan, Taiwan. E-mail: gjchang{at}adm.cgmh.org.tw