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 eectively suppressed the ischaemia-reperfusion induced polymorphic ventricular tachyrhythmias in adult rat heart (EC 50 =2.8 mM). 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 I Na (IC 50 =4.1 mM) 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 Ca 2+ current (I Ca ) was also reduced, but to a lesser degree (IC 50 =5.3 mM, maximal inhibition=31.8%). 4 This agent also in¯uenced 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 ) (IC 50 =2.9 mM) and a slowly inactivating, steady-state outward current (I ss ) (IC 50 =2.5 mM). 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 signi®cant negative shift of the voltage-dependent steady-state inactivation curve but did not aect its rate of recovery from inactivation. 5 At higher concentrations, the inward recti®er K + current (I K1 ) was also inhibited but to a less extent. Its slope conductance after 3, 10 and 30 mM 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 Ca 2+ and I K1 channels. These changes alter the electrophysiological properties of the heart and terminate the ischaemia reperfusion induced ventricular arrhythmia. The signi®cant I to inhibition and minimal I Ca suppression may aord an opportunity to develop an eective antiarrhythmic agent linked with positive inotropy.

Induction of contracture and extracellular Ca2+ influx in cardiac muscle by sanguinarine: a study on cardiotoxicity of sanguinarine

“…The method was according to Su et al [18]. Male Wistar rats (weighing 250-350 g) were purchased from the Animal Center of the College of Medicine, National Taiwan University, Taipei, Taiwan.…”

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

“…This effect is consistent with the inhibition of the I Na by this agent, which likely contributes to the antiarrhythmic and AERP and His-Purkinje system functional refractory period prolongation actions by this agent. In rat ventricular myocytes, our previous report showed that HA-7 exerted usedependent inhibition on I Na and may bind preferentially to the inactivated state of Na ϩ channels (Su et al, 1997). In this context, the greater V max -suppressing effect of HA-7 in atria than in papillary muscles may be explained by the less negative resting membrane potential and more prominent druginduced APD prolongation of atrial tissues.…”

“…In the same study, it was shown that this antiarrhythmic activity may be related to the predominant blockade of the transient outward K ϩ current (I to ), a major repolarizing current in rat heart (Josephson et al, 1984), steady-state outward K ϩ current (I SS ), and Na ϩ channels. Thus, HA-7 may exert mixed class I and stronger class III antiarrhythmic properties (Su et al, 1997). In fact, most of the class III antiarrhythmic agents, such as sotalol, dofetilide, or amiodarone, are known to prolong cardiac APD and suppress re-entrant arrhythmia primarily via the blockade of the I K , which is absent in rat cardiomyocytes but exists prominently as the main repolarizing current in guinea pig (Hume and Uehara, 1985) and human myocardium (Li et al, 1996).…”

“…We previously demonstrated that HA-7 could reverse the cardiac arrhythmias induced by postischemic reperfusion in isolated rat hearts and produce a moderate positive inotropic effect in rat cardiac tissues (Su et al, 1997). In the same study, it was shown that this antiarrhythmic activity may be related to the predominant blockade of the transient outward K ϩ current (I to ), a major repolarizing current in rat heart (Josephson et al, 1984), steady-state outward K ϩ current (I SS ), and Na ϩ channels.…”

LMBD1 Protein Serves as a Specific Adaptor for Insulin Receptor Internalization

“…Primary rat ventricular cardiomyocytes were isolated as described previously (21,22). In brief, ventricles were isolated from 25 neonatal rat hearts.…”