Confirmation of a proarrhythmic risk underlying the clinical use of common Chinese herbal intravenous injections.
BACKGROUND
The Chinese herbal intravenous injections (CHI) which are extracted from herb(s) are used clinically in China as putative therapies for a variety of diseases.


OBJECTIVE
The 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.


METHODS
In vivo and in vitro guinea pig electrocardiogram, intracellular action potential and patch clamp recording techniques were carried out.


RESULTS
Both 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 Ca(2+) current from left ventricular myocytes of guinea pig, hNav1.5 current and hERG current with 50% inhibiting concentrations (IC(50)) of 6.0, 3.0 and 10.7 times CRC, respectively. Also, QKL significantly suppressed L-type Ca(2+) and hNav1.5 currents with IC(50)s of 10.7 and 13.8 times CRC. YZH significantly suppressed L-type Ca(2+), hNav1.5 and hERG currents with IC(50)s of 12.1, 32.9 and 141.7 times CRC, respectively.


CONCLUSIONS
The three CHIs studied caused bradyarrhythmia mainly by inhibiting Na(+) current and L-type Ca(2+) current.
National Standard Laboratory of Pharmacology for Chinese Materia Medica, Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210046, China. longchen@njutcm.edu.cn
Long
L
Chen
Tom
T
Titch
Zhuoka
Z
Luo
Yi
Y
Xu
Xuehua
X
Li
Feifei
F
Huang
Lei
L
Liu
Wei
W
Xiao
Hao
H
Wu
Zhongyue
Z
Wang
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000503:physiopathology; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000009:adverse effects*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000502:physiology; D006168:Guinea Pigs; D057809:HEK293 Cells; D006352:Heart Ventricles / Q000166:cytology; D006801:Humans; D007275:Injections, Intravenous; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000502:physiology; D010210:Papillary Muscles / Q000187:drug effects / Q000503:physiopathology; D008517:Phytotherapy / Q000009:adverse effects*; D012306:Risk
D004365:Drugs, Chinese Herbal; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D062554:NAV1.5 Voltage-Gated Sodium Channel; C504928:Qingkailing; C568320:SCN5A protein, human; C516400:shuang-huang-lian; C070600:yin zhi huang