Ion channel mechanism and ingredient bases of Shenfu Decoction's cardiac electrophysiological effects

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Abstract

Aim of the study

Ion channel mechanism of cardiac electrophysiological effects of Shenfu Decoction (SFD, Ginseng and Aconiti Praeparatae Decoction), a traditional Chinese medicine (TCM) prescription, and its ingredient bases were investigated in guinea pigs.

Materials and methods

After administration of an injection made from SFD (Shenfu Injection, SFI), the indexes of transmembrane action potential (TAP) in vivo and sodium channels in isolated ventricular myocyte were assayed by suspended microelectrodes and patch clamp techniques respectively, and ingredients of SFD were compared with.

Results

After administration of SFI, the action potential amplitude (APA) and maximum velocity (Vmax) of TAP decreased. In the presence of either SFI or Fuzi active ingredient (FZAI)(5, 10, and 15%), not any other ingredient, the density of voltage-dependent sodium current (INa) decreased significantly, while the inhibition ratio of SFI was larger. EC50 of SFI was less than the one of FZAI, and SFI displayed effects on INa in wider voltage scope than FZAI in current-voltage curve. Both SFI and FZAI shifted the steady-state inactivation curve of sodium channels to the left, and the recovery curve to the right.

Conclusions

The results indicated that the cardiac electrophysiological effects of SFI were exerted by blocking sodium channels, and FZAI contributed to such effects most but inferior to SFI, which justified its use in anti-arrhythmia, myocardial protection, etc.

Introduction

Cardiovascular disease (CVD) is a health concern worldwide. The World Health Organization has estimated that 17.5 million people died of CVD in 2005, representing 30% of all global deaths. 3 million people died of CVD annually in China, which has become the number one cause of death nationally (Hu and Kong, 2006). More than 50% of all CVD deaths derived from sudden cardiac death, the most common cause of which is malignant arrhythmia, which also plays important roles in ischemic heart disease (prevalence rate being 0.46% in China), myocardial infarction, cardia failure (prevalence rate being 0.8–1.1% in China) and so on (Ye and Lu, 2004). It is urgent to develop more related cardiac active drugs with high performance and less side effects.

In traditional Chinese societies, phytotherapy is highly valued and widely utilized, and partly proved to have less side effects than western medicine to a certain degree. Shenfu Decoction (SFD, Ginseng and Aconiti Praeparatae Decoction) is a traditional Chinese medicine (TCM) prescription documented first in 1465, which consists of Ginseng (Panax, family: Araliaceae) and Fuzi (Radix Aconiti Lateralis Preparata, Aconitum carmichaeli Debx., family: Ranunculaceae) (Sheng et al., 2006). Ginseng is the root of Panax ginseng C.A. Mey, and Fuzi is the daughter root of Aconitum carmichaeli Debx. Both of them have been commonly used herbal medicine in China ever since 1800 years ago: Ginseng mainly as a tonic for great nourishment of renal qi and Fuzi for reviving Yang. SFD is a combination of the two and performs significant predominance in the folk treatment of diseases with the sign of Yangqi decline or Yang exhaustion, such as circulatory collapse, shock, thoracic obstruction, acute thoracic pain, and so on (i.e. mainly CVD).

Shenfu Injection (SFI) is a typical form of SFD for intravenous medication, made from raw material of this decoction with patent processing technology, whose quality is controlled strictly according to the standard of China Ministry of Public Health. SFI has been used for treatment of many kinds of diseases, especially being famous for its traditional cardiovascular protective effectiveness, such as improving heart function, stretching aeteria coronaria, stabilizing blood pressure, easing ischemia reperfusion injury (IRI) so as to treat coronary artery disease, myocardial infarct, cardia insufficiency, and arrhythmia (Dong et al., 2004, Su et al., 2005, Li, 2006, Li et al., 2007). SFI can prevent and cure many kinds of arrhythmia (both tachyar and lentor, Wang et al., 2001), whose such two-way regulating effect has rarely been found in western medicine, deserving further studies, which may shed light on exploitation of new drugs. The electrophysiological characteristics and ion channels on myocyte membrane are the main targets for anti-arrhythmia pharmacological research. However, to the authors’ knowledge, except for report on panaxsaponin's blocking effect on calcium channels (Zhang et al., 1994, Zhong and Jiang, 1997, Choi et al., 2001), few studies related to SFI's direct effects on membrane ion channels have been reported up till now and the molecular mechanism underlying anti-arrhythmia effect of SFI was not clear. Moreover, SFI, like many other complex prescriptions of TCM, was also found to be more effective than any of its ingredient used separately in vivo (Zhen et al., 2004).

In recent years, by the tendency of modernization of traditional medicine, advanced techniques with scientific precision have been used in this field and found helpful. In this study, we tested SFI's effects on cardiac electrophysiology in vivo and related ion channels in single ventricular myocyte compared with SFI's main ingredients by microelectrodes and patch clamp techniques, respectively, so as to reveal its molecular electrophysiological mechanism and active material bases.

Section snippets

Drugs and animals

SFI (Batch No.: 060301, 1 ml equaled to crude drug Ginseng 0.1 g and Radix Aconiti Lateralis Preparata 0.2 g) was purchased from Ya’an Sanjiu Medicine Co. Ltd., Sichuan, China. Fuzi active ingredient (FZAI, containing the same ingredient of Radix Aconiti Lateralis Preparata as SFI without Ginseng ingredient), Hongshen active ingredient (HSAI, containing the same ingredient of Ginseng as SFI without Fuzi ingredient), and adjuvant (remained solution before SFI being added FZAI and HSAI into in the

Effect of SFI on TAP in vivo

Action potential duration (APD) was measured at 10, 50 and 90% repolarization (APD10, APD50, and APD90). Other indexes for observing included: action potential amplitude (APA), maximum velocity (Vmax), rest potential (RP), overshoot (OS). APD10, APD50, APD90, RP, and OS were not significantly affected by varying dosages of SFI. Typical intraperitoneal injection of SFI (15 ml/kg body weight, compared with saline) did, however, significantly decrease APA and Vmax, from (76.8 ± 2.3) to (69.0 ± 2.3) mV (P

Discussion and conclusions

In this study, the result of regulatory effect of SFI on transmembrane action potential and voltage-dependent sodium channels in ventricular myocytes was presented. The result showed: SFI decreased TAP amplitude and maximum velocity of depolarizing phase without influencing TAP duration, repolarization, etc.; it diminished the current density of INa in a concentration-dependent manner with a “ceiling effect” fitted well by the Hill function, and it shifted current–voltage curve of INa upwards;

Acknowledgements

The work was supported by a Science and Technology Grant of China Association of Chinese Medicine(No. 200602-15JC-10) and Research Foundation of Chongqing Medical University (No. 1273-33264). The authors thank Mr. Xiao-rong Zeng for helpful advices, and Mr. Ya-ning Zhu and Mr. Zhi Lu for helpfully offering some drugs.

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