Confirmation of a proarrhythmic risk underlying the clinical use of common Chinese herbal intravenous injections

Abstract

Ethnopharmacological relevanceThe Chinese herbal intravenous injections (CHI) which are extracted from herb(s) are used clinically in China as putative therapies for a variety of diseases. Aim of the studyThe mechanism(s) which underline findings of severe adverse drug reactions (ADR) noted in more than a thousand published articles on CHIs, are still poorly understood. With 109 CHIs currently in clinical use, we investigated the proarrhythmic effects of three specific CHIs, Shuanghuanglian (SHL), Qingkailing (QKL) and Yinzhihuang (YZH), using in vivo and in vitro ion channel models. Materials and methodsIn vivo and in vitro guinea pig electrocardiogram, intracellular action potential and patch clamp recording techniques were carried out. ResultsBoth SHL and QKL (both in one, five and ten times clinically relevant doses (CRD) for in vivo and clinically relevant concentrations (CRC) for in vitro) prolonged P–R intervals in a dose or concentration-dependent manner and SHL also prolonged QTc. YZH (ten and 20 times CRD and CRC) prolonged P–R intervals without changing QTc. Intracellular action potential recordings from guinea pig papillary muscle indicated SHL and QKL abolished the firing of action potentials at ten and 30 times CRC respectively. SHL significantly suppressed L-type Ca2+ current from left ventricular myocytes of guinea pig, hNav1.5 current and hERG current with 50% inhibiting concentrations (IC50) of 6.0, 3.0 and 10.7 times CRC, respectively. Also, QKL significantly suppressed L-type Ca2+ and hNav1.5 currents with IC50s of 10.7 and 13.8 times CRC. YZH significantly suppressed L-type Ca2+, hNav1.5 and hERG currents with IC50s of 12.1, 32.9 and 141.7 times CRC, respectively. ConclusionsThe three CHIs studied caused bradyarrhythmia mainly by inhibiting Na+ current and L-type Ca2+ current.