27 November 1997, Volume 122, Issue 7, Pages 1285 – 1298

Paper

Electrophysiological basis for the antiarrhythmic action and positive inotropy of HA-7, a furoquinoline alkaloid derivative, in rat heart Ming-Jai Su1,4, Gwo-Jyh Chang1, Mei-Hwan Wu2 & Sheng-Chu Kuo3 1Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan     2Department of Pediatrics, College of Medicine, National Taiwan University, Taipei, Taiwan     3Institute of Pharmaceutical Chemistry, China Medical College, Taichung, Taiwan     4Author for correspondence Present address: Pharmacological Institute, College of Medicine, National Taiwan University, No. 1, Sec. 1, Jen-Ai Road, Taipei, Taiwan

Keywords

HA-7;   furoquinoline derivative;   cardiac arrhythmia;   positive inotropy;   action potential;   Na+;   Ca2+ and K+ currents;   cardiac myocytes

Abstract

1   HA-7, a new synthetic derivative of furoquinoline alkaloid, increased the contractile force of right ventricular strips and effectively suppressed the ischaemia-reperfusion induced polymorphic ventricular tachyrhythmias in adult rat heart (EC50=2.8 µM). 2   In rat ventricular myocytes, HA-7 concentration-dependently prolonged the action potential duration (APD) and decreased the maximal rate of rise of the action potential upstroke (V¨max). The action potential amplitude and resting membrane potential were also reduced, but to a smaller extent. The prolongation of APD by HA-7 was prevented by pretreating the cells with 1 mM 4-AP. 3   Voltage clamp experiments revealed that HA-7 decreased the maximal current amplitude of INa (IC50=4.1 µM) and caused a negative shift of its steady-state inactivation curve and slowed its rate of recovery from inactivation. The use-dependent inhibition of INa by HA-7 was enhanced at a higher stimulation rate. The L-type Ca2+ current (ICa) was also reduced, but to a lesser degree (IC50=5.3 µM, maximal inhibition=31.8%). 4   This agent also influenced the time- and voltage-dependent K+ currents. The prolongation of APD was associated with an inhibition of a 4-AP sensitive transient outward K+ current (Ito) (IC50=2.9 µM) and a slowly inactivating, steady-state outward current (Iss) (IC50=2.5 µM). The inhibition of Ito by HA-7 was associated with an acceleration of its time constant of inactivation. HA-7 suppressed Ito in a time-dependent manner and caused a significant negative shift of the voltage-dependent steady-state inactivation curve but did not affect its rate of recovery from inactivation. 5   At higher concentrations, the inward rectifier K+ current (IK1) was also inhibited but to a less extent. Its slope conductance after 3, 10 and 30 µM HA-7 was decreased by 24±4%, 41±5% and 54±8%, respectively. 6   We conclude that HA-7 predominantly blocks Ito and Na+ channels and that it also weakly blocks Ca2+ and IK1 channels. These changes alter the electrophysiological properties of the heart and terminate the ischaemia reperfusion induced ventricular arrhythmia. The significant Ito inhibition and minimal ICa suppression may afford an opportunity to develop an effective antiarrhythmic agent linked with positive inotropy.

Received 23 July, 97; Accepted 28 August, 97

^© Macmillan Publishers Ltd 1997