Dehydroevodiamine and hortiamine, alkaloids from the traditional Chinese herbal drug Evodia rutaecarpa, are IKr blockers with proarrhythmic effects in vitro and in vivo

Igor Baburin,Rosanne Varkevisser,Anja Schramm,Priyanka Saxena,Stanislav Beyl,Phillip Szkokan,Tobias Linder,Anna Stary-Weinzinger,Marcel A.G Van Der Heyden,Marien Houtman,Hiroki Takanari,Malin Jonsson,Jet H.D Beekman,Matthias Hamburger,Marc A Vos,Steffen Hering

doi:10.1016/j.phrs.2018.02.024

Abstract

Evodiae fructus is a widely used herbal drug in traditional Chinese medicine. Evodia extract was found to inhibit hERG channels. The aim of the current study was to identify hERG inhibitors in Evodia extract and to investigate their potential proarrhythmic effects. Dehydroevodiamine (DHE) and hortiamine were identified as IKr (rapid delayed rectifier current) inhibitors in Evodia extract by HPLC-microfractionation and subsequent patch clamp studies on human embryonic kidney cells. DHE and hortiamine inhibited IKr with IC50s of 253.2±26.3nM and 144.8±35.1nM, respectively. In dog ventricular cardiomyocytes, DHE dose-dependently prolonged the action potential duration (APD). Early afterdepolarizations (EADs) were seen in 14, 67, 100, and 67% of cells after 0.01, 0.1, 1 and 10μM DHE, respectively. The proarrhythmic potential of DHE was evaluated in 8 anesthetized rabbits and in 8 chronic atrioventricular block (cAVB) dogs. In rabbits, DHE increased the QT interval significantly by 12±10% (0.05mg/kg/5min) and 60±26% (0.5mg/kg/5min), and induced Torsade de Pointes arrhythmias (TdP, 0.5mg/kg/5min) in 2 rabbits. In cAVB dogs, 0.33mg/kg/5min DHE increased QT duration by 48±10% (P<0.05*) and induced TdP in 2/4 dogs. A higher dose did not induce TdP. In human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), methanolic extracts of Evodia, DHE and hortiamine dose-dependently prolonged APD. At 3μM DHE and hortiamine induced EADs.hERG inhibition at submicromolar concentrations, APD prolongation and EADs in hiPSC-CMs and dose-dependent proarrhythmic effects of DHE at micromolar plasma concentrations in cAVB dogs should increase awareness regarding proarrhythmic effects of widely used Evodia extracts.

Highlights

To assess the risk of human Ether-a-go-go Related Gene (hERG) channel inhibition by medicinal plants, we screened a library of extracts prepared from major herbal drugs of the European and Chinese Pharmacopoeias
Application of 100 ␮g/mL extract to human embryonic kidney (HEK) 293 cells stably expressing hERG channels induced 85.2 ± 0.5% (n = 4) inhibition of the potassium current
Subsequent analysis revealed that the hERG channel inhibitory activity of crude Evodia extract was attributable to DHE (1) and hortiamine (3)

Summary

Introduction

Wu Zhu Yu, the dried and nearly ripe fruit of Evodia rutaecarpa, is among the most popular and widely used herbal drugs in TCM. It is used as an analgesic, anti-emetic, for treatment of headache, gastrointestinal disorders, and menstrual complaints, or by means of external application against mouth ulcers [1]. Baburin et al / Pharmacological Research 131 (2018) 150–163 to which new drug molecules are subjected, herbal drugs are considered as safe on the basis of empirical knowledge from use over centuries This may be an issue, in particular, with herbal drugs containing pharmacologically potent molecules, such as is the case for some TCM herbs. Use of some TCM herbal preparations have been associated with severe side effects, and even deaths due to organ failure, as was the case with a slimming product containing Aristolochia fanchi, an herbal drug with well-understood nephrotoxic liabilities [4]

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