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Effects of mixed herbal extracts from parched Puerariae radix, gingered Magnoliae cortex, Glycyrrhizae radix and Euphorbiae radix (KIOM-79) on cardiac ion channels and action potentials.

Park SJ, Choi KS, Shin DH, Kim JS, Jang DS, Youm JB, Choe H, Earm YE, Kim SJ - J. Korean Med. Sci. (2009)

Bottom Line: Consistent with the decreased V(max) and plateau potential, the peak amplitude of Na+ current (I(Na)) and Ca2+ current (I(Ca,L)) were decreased by KIOM-79.KIOM-79 showed dual effects on hERG K+ current; increase of depolarization phase current (I(depol)) and decreased tail current at repolarization phase (I(tail)).The increase of APD was suspected due to the decreased I(tail).

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Seoul National University College of Medicine, Seoul, Korea.

ABSTRACT
KIOM-79, a mixture of ethanol extracts from four herbs (parched Puerariae radix, gingered Magnoliae cortex, Glycyrrhizae radix and Euphorbiae radix), has been developed for the potential therapeutic application to diabetic symptoms. Because screening of unexpected cardiac arrhythmia is compulsory for the new drug development, we investigated the effects of KIOM-79 on the action potential (AP) and various ion channel currents in cardiac myocytes. KIOM-79 decreased the upstroke velocity (V(max)) and plateau potential while slightly increased the duration of action potential (APD). Consistent with the decreased V(max) and plateau potential, the peak amplitude of Na+ current (I(Na)) and Ca2+ current (I(Ca,L)) were decreased by KIOM-79. KIOM-79 showed dual effects on hERG K+ current; increase of depolarization phase current (I(depol)) and decreased tail current at repolarization phase (I(tail)). The increase of APD was suspected due to the decreased I(tail). In computer simulation, the change of cardiac action potential could be well simulated based on the effects of KIOM-79 on various membrane currents. As a whole, the influence of KIOM-79 on cardiac ion channels are minor at concentrations effective for the diabetic models (0.1-10 microg/mL). The results suggest safety in terms of the risk of cardiac arrhythmia. Also, our study demonstrates the usefulness of the cardiac computer simulation in screening drug-induced long-QT syndrome.

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Computer simulation of the effects of KIOM-79 on the voltage-dependence of hERG channel activity. (A) A proposed change in voltage-dependence of steady-state inactivation of hERG to reproduce the effects of KIOM-79 on hERG current in Fig. 4. In order to reduce the slope of the voltage-dependence of steady-state inactivation, the opening and closing rate constants were modified as follows. αh=1.0/{1.6*exp([Vm-10]/17.0)+0.7*exp([Vm-10]/300.0)}; βh=1.0/{0.067*exp(-[Vm+30]/17.0)+0.63*exp(-[Vm+30]/150.0)}. The voltage-dependence of opening rate constant was shifted to the right by 10 mV, while that of closing rate constant was shifted to the left by 30 mV. Note that the voltage-dependence shows a deviation from typical Boltzman distribution since there are two exponential terms in the equations describing αh and βh. (B) Reconstructed hERG currents from the altered rate constants of inactivation. Altered inactivation increased the amplitude of membrane current activated by a depolarizing step from -80 mV to +20 mV, whereas it reduced the amplitude of membrane current activated by a repolarizing step from +20 to -50 mV.
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Figure 6: Computer simulation of the effects of KIOM-79 on the voltage-dependence of hERG channel activity. (A) A proposed change in voltage-dependence of steady-state inactivation of hERG to reproduce the effects of KIOM-79 on hERG current in Fig. 4. In order to reduce the slope of the voltage-dependence of steady-state inactivation, the opening and closing rate constants were modified as follows. αh=1.0/{1.6*exp([Vm-10]/17.0)+0.7*exp([Vm-10]/300.0)}; βh=1.0/{0.067*exp(-[Vm+30]/17.0)+0.63*exp(-[Vm+30]/150.0)}. The voltage-dependence of opening rate constant was shifted to the right by 10 mV, while that of closing rate constant was shifted to the left by 30 mV. Note that the voltage-dependence shows a deviation from typical Boltzman distribution since there are two exponential terms in the equations describing αh and βh. (B) Reconstructed hERG currents from the altered rate constants of inactivation. Altered inactivation increased the amplitude of membrane current activated by a depolarizing step from -80 mV to +20 mV, whereas it reduced the amplitude of membrane current activated by a repolarizing step from +20 to -50 mV.

Mentions: Among the parameters describing the kinetics of hERG activation and inactivation, a modification of parameters related to inactivation was crucial to the reproducing the effects of KIOM-79 on hERG current. To mimic the changes of recorded hERG current by KIOM-79, we shifted the voltage-dependence of opening and closing rate constants related with the inactivation process to the right by 10 mV and to the left by 30 mV, respectively. By this, the voltage-dependence of steady-state inactivation was reduced (Fig. 6A), and the dual effects of KIOM-79 on Idepol at 20 mV and on Itail at -50 mV were reproduced (Fig. 6B) similar with the recordings shown in Fig. 4A.


Effects of mixed herbal extracts from parched Puerariae radix, gingered Magnoliae cortex, Glycyrrhizae radix and Euphorbiae radix (KIOM-79) on cardiac ion channels and action potentials.

Park SJ, Choi KS, Shin DH, Kim JS, Jang DS, Youm JB, Choe H, Earm YE, Kim SJ - J. Korean Med. Sci. (2009)

Computer simulation of the effects of KIOM-79 on the voltage-dependence of hERG channel activity. (A) A proposed change in voltage-dependence of steady-state inactivation of hERG to reproduce the effects of KIOM-79 on hERG current in Fig. 4. In order to reduce the slope of the voltage-dependence of steady-state inactivation, the opening and closing rate constants were modified as follows. αh=1.0/{1.6*exp([Vm-10]/17.0)+0.7*exp([Vm-10]/300.0)}; βh=1.0/{0.067*exp(-[Vm+30]/17.0)+0.63*exp(-[Vm+30]/150.0)}. The voltage-dependence of opening rate constant was shifted to the right by 10 mV, while that of closing rate constant was shifted to the left by 30 mV. Note that the voltage-dependence shows a deviation from typical Boltzman distribution since there are two exponential terms in the equations describing αh and βh. (B) Reconstructed hERG currents from the altered rate constants of inactivation. Altered inactivation increased the amplitude of membrane current activated by a depolarizing step from -80 mV to +20 mV, whereas it reduced the amplitude of membrane current activated by a repolarizing step from +20 to -50 mV.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2698184&req=5

Figure 6: Computer simulation of the effects of KIOM-79 on the voltage-dependence of hERG channel activity. (A) A proposed change in voltage-dependence of steady-state inactivation of hERG to reproduce the effects of KIOM-79 on hERG current in Fig. 4. In order to reduce the slope of the voltage-dependence of steady-state inactivation, the opening and closing rate constants were modified as follows. αh=1.0/{1.6*exp([Vm-10]/17.0)+0.7*exp([Vm-10]/300.0)}; βh=1.0/{0.067*exp(-[Vm+30]/17.0)+0.63*exp(-[Vm+30]/150.0)}. The voltage-dependence of opening rate constant was shifted to the right by 10 mV, while that of closing rate constant was shifted to the left by 30 mV. Note that the voltage-dependence shows a deviation from typical Boltzman distribution since there are two exponential terms in the equations describing αh and βh. (B) Reconstructed hERG currents from the altered rate constants of inactivation. Altered inactivation increased the amplitude of membrane current activated by a depolarizing step from -80 mV to +20 mV, whereas it reduced the amplitude of membrane current activated by a repolarizing step from +20 to -50 mV.
Mentions: Among the parameters describing the kinetics of hERG activation and inactivation, a modification of parameters related to inactivation was crucial to the reproducing the effects of KIOM-79 on hERG current. To mimic the changes of recorded hERG current by KIOM-79, we shifted the voltage-dependence of opening and closing rate constants related with the inactivation process to the right by 10 mV and to the left by 30 mV, respectively. By this, the voltage-dependence of steady-state inactivation was reduced (Fig. 6A), and the dual effects of KIOM-79 on Idepol at 20 mV and on Itail at -50 mV were reproduced (Fig. 6B) similar with the recordings shown in Fig. 4A.

Bottom Line: Consistent with the decreased V(max) and plateau potential, the peak amplitude of Na+ current (I(Na)) and Ca2+ current (I(Ca,L)) were decreased by KIOM-79.KIOM-79 showed dual effects on hERG K+ current; increase of depolarization phase current (I(depol)) and decreased tail current at repolarization phase (I(tail)).The increase of APD was suspected due to the decreased I(tail).

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Seoul National University College of Medicine, Seoul, Korea.

ABSTRACT
KIOM-79, a mixture of ethanol extracts from four herbs (parched Puerariae radix, gingered Magnoliae cortex, Glycyrrhizae radix and Euphorbiae radix), has been developed for the potential therapeutic application to diabetic symptoms. Because screening of unexpected cardiac arrhythmia is compulsory for the new drug development, we investigated the effects of KIOM-79 on the action potential (AP) and various ion channel currents in cardiac myocytes. KIOM-79 decreased the upstroke velocity (V(max)) and plateau potential while slightly increased the duration of action potential (APD). Consistent with the decreased V(max) and plateau potential, the peak amplitude of Na+ current (I(Na)) and Ca2+ current (I(Ca,L)) were decreased by KIOM-79. KIOM-79 showed dual effects on hERG K+ current; increase of depolarization phase current (I(depol)) and decreased tail current at repolarization phase (I(tail)). The increase of APD was suspected due to the decreased I(tail). In computer simulation, the change of cardiac action potential could be well simulated based on the effects of KIOM-79 on various membrane currents. As a whole, the influence of KIOM-79 on cardiac ion channels are minor at concentrations effective for the diabetic models (0.1-10 microg/mL). The results suggest safety in terms of the risk of cardiac arrhythmia. Also, our study demonstrates the usefulness of the cardiac computer simulation in screening drug-induced long-QT syndrome.

Show MeSH
Related in: MedlinePlus