Abstract 8917: Dauricine Suppresses Early Afterdepolarizations and Torsade De Pointes In Rabbit Hearts with Long Qt2 Syndrome
Background: Dauricine (Dau) is a bisbenzylisoquinoline alkaloid derivative isolated from rhizome of Mensipermum dauricium DC, a Chinese herb. Dau has been shown to lower blood pressure, platelet aggregation, inflammatory response and arrhythmia. Dau has also been shown to inhibit the late Na+ current, INaL, IKr and L-type Ca2+ current, ICaL by shifting the steady state inactivation and activation curves and prolonging the τ value of recovery.
Objectives: The multiple targets of Dau make it challenging to explain the suppression of early afterdepolarizations (EADs) and Torsade de Pointes (TdP) in drug-induced Long QT 2 (LQT2) model in rabbit hearts by mapping Action Potential (AP) and Ca2+ transients (CaiT) and to mathematically model the effect of Dau and explain its possible mode of action.
Methods: Experimental (Langendorff rabbit hearts labelled with Rhod-2/AM and PGH1 to simultaneously map Action Potential (AP) and Ca2+ transients (CaiT)) and simulations (Shannon et al. model) of rabbit AP and CaiT were used to investigate the effects of Dau (5µM) before and after LQT2 induced with Dofetilide (Dofe=0.5μ M) to block IKr.
Results: In controls, Dau tended to prolong AP durations (APDs), CaiT durations (CTD) (p>0.5) but significantly reduced conduction velocity (CV) (p<0.05; n=5) in a rate independent manner. In LQT2, Dofe prolonged APDs (318±24 to 835±32 ms; p<0.01), CTDs (346±36 to 867±48ms; p<0.01) elicited EADs and TdP that were suppressed by Dau (p<0.01; n=5/5 hearts). Dau (5µM) reduced the Dofe-prolongation of APDs (835±32 to 542±93ms; p<0.01) and CTD (867±48 to 567±103ms; p<0.01) and reversed the Dofe-prolongation of Dispersion of Repolarization (DOR) (25±6 to 55± 15ms; p<0.01; reversed 55±15ms to 29±15ms; p<0.05). Simulations of the effects of Dofe, Dau and Dofe + Dau indicate that Dau's suppression of EADs is primarily mediated by reducing the Cai overload by modifying the kinetics of ICaL.
Conclusions: Dau (5µM) markedly reduced CV and in LQT2 significantly shortening APDs, CTDs, reduced DOR and suppressed EADs and TdP. Simulations implicate the slowing down of activation and inactivation kinetics of ICaL as the dominant anti-arrhythmic mechanism.
- © 2011 by American Heart Association, Inc.