ELECTROPHYSIOLOGICAL BASIS FOR THE ANTIARRHYTHMIC ACTION AND POSITIVEINOTROPY OF HA-7, A FUROQUINOLINE ALKALOID DERIVATIVE, IN RAT-HEART

1 HA-7, a new synthetic derivative of furoquinoline alkaloid, increase d the contractile force of right ventricular strips and effectively su ppressed the ischaemia-reperfusion induced polymorphic ventricular tac hyrhythmias in adult rat heart (EC50=2.8 mu M). 2 In rat ventricular m yocytes, HA-7 concentration-dependently prolonged the action potential duration (APD) and decreased the maximal rate of rise of the action p otential upstroke (V-max). The action potential amplitude and resting membrane potential were also reduced, but to a smaller extent. The pro longation 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 mu M) and caused a negati ve shift of its steady-state inactivation curve and slowed its rate of recovery from inactivation. The use-dependent inhibition of I-Na by H A-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 mu M, maxim al inhibition=31.8%). 4 This agent also influenced the time-and voltag e-dependent K+ currents. The prolongation of APD was associated with a n inhibition of a 4-AP sensitive transient outward K+ current (I-to) ( IC50=2.9 mu M) and a slowly inactivating, steady-state outward current (I-ss) (IC50=2.5 mu M). The inhibition of I-to by HA-7 was associated with an acceleration of its time constant of inactivation. HA-7 suppr essed I-to in a time-dependent manner and caused a significant negativ e shift of the voltage-dependent steady-state inactivation curve but d id not affect its rate of recovery from inactivation. 5 At higher conc entrations, the inward rectifier K+ current (I-K1) was also inhibited but to a less extent. Its slope conductance after 3, 10 and 30 mu M HA -7 was decreased by 24+/-4%, 41+/-5% and 54+/-8%, respectively. 6 We c onclude 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 ischaem ia reperfusion induced ventricular arrhythmia. The significant I-to in hibition and minimal I-Ca suppression may afford an opportunity to dev elop an effective antiarrhythmic agent linked with positive inotropy.