Electrophysiological basis for the antiarrhythmic action and positive inotropy of HA-7, a furoquinoline alkaloid derivative, in rat heart.

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 microM). 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 (Vmax). 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 I(Na) (IC50 = 4.1 microM) and caused a negative shift of its steady-state inactivation curve and slowed its rate of recovery from inactivation. The use-dependent inhibition of I(Na) by HA-7 was enhanced at a higher stimulation rate. The L-type Ca2+ current (I(Ca)) was also reduced, but to a lesser degree (IC50 = 5.3 microM, 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 (I(to)) (IC50 = 2.9 microM) and a slowly inactivating, steady-state outward current (I(SS)) (IC50 = 2.5 microM). The inhibition of I(to) by HA-7 was associated with an acceleration of its time constant of inactivation. HA-7 suppressed I(to) 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 (I(KI)) was also inhibited but to a less extent. Its slope conductance after 3, 10 and 30 microM HA-7 was decreased by 24+/-4%, 41+/-5% and 54+/-8%. respectively. 6. We conclude that HA-7 predominantly blocks I(to) and Na+ channels and that it also weakly blocks Ca2+ and I(KI) channels. These changes alter the electrophysiological properties of the heart and terminate the ischaemia reperfusion induced ventricular arrhythmia. The significant I(to) inhibition and minimal I(Ca) suppression may afford an opportunity to develop an effective antiarrhythmic agent linked with positive inotropy.