Abstract 8917: Dauricine Suppresses Early Afterdepolarizations and Torsade De Pointes In Rabbit Hearts with Long Qt2 Syndrome

Abstract

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, I NaL , I Kr and L-type Ca 2+ current, I CaL 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 Ca 2+ transients (Ca i T) 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 Ca 2+ transients (Ca i T)) 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 I Kr . 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 Ca i overload by modifying the kinetics of I CaL . 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 I CaL as the dominant anti-arrhythmic mechanism.