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First published on September 20, 2005; DOI: 10.1124/jpet.105.092106

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Received for publication July 7, 2005.
Revised September 7, 2005.
Accepted for publication September 15, 2005.

Multiple Cellular Electrophysiological Effects of a Novel Antiarrhythmic Furoquinoline Derivative HA-7, in Guinea Pig Cardiac Preparations

Gwo-Jyh Chang 1*, Ming-Jai Su 2, Sheng-Chu Kuo 3, Tsung-Pin Lin 3, Ying-Shiung Lee 4

1 Graduate Institute of Clinical Medicinal Sciences, College of Medicine, Chang Gung University 2 Pharmacological Institute, College of Medicine, National Taiwan University 3 Institute of Pharmaceutical Chemistry, China Medical University 4 The First Cardiovascular Division of Medicine, Chang Gung Memorial Hospital

* Address correspondence to: E-mail: gjchang{at}adm.cgmh.org.tw

Abstract

We studied the electrophysiological and antiarrhythmic actions of HA-7, 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 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 while 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 (IKs) (IC50=4.8 µM) and fast component (IKr) (IC50=1.1 µM) of the delayed rectifier K+ currents. Similar results could also be observed in atrial myocytes. The inward rectifier K+ current (IK1) was also reduced somewhat by HA-7. HA-7 also suppressed the Na+ inward current (INa) (IC50=2.9 µM) and inhibited the L-type Ca2+ current (ICa) (IC50=4.0 µM, maximal inhibition=69%) to a lesser extent. We conclude that HA-7 blocks multiple ionic currents and that these affect the electrophysiological properties of the conduction system as well as the myocardial tissues and may contribute to its antiarrhythmic efficacy.


Key words: HA-7 (N-benzyl-7-methoxy-2,3,4,9-tetrahydrofuro[2,3-b]quinoline-3,4-dione, action potential, cardiac arrhythmias, cardiac electrophysiology, ionic channels, patch clamp




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