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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 changes in AP shape by altered properties of hERG, INa and ICaL channels. (A) Changes in AP shape by applying the altered inactivation of hERG (Fig. 6) and the decrease in Na+-channel density (75% of control) to the computational model. By this modification, the APD90 of reconstructed action potential was prolonged from 208.7 to 230.7 msec, and the peak amplitude of phase 0 was decreased, similar with the results from Fig. 1. (B) When the conductance of ICaL was reduced (80% of control) in addition to the above changes in hERG and INa, the plateau potential was also affected reproducing the results from the cardiac Purkinje fiber of rabbits. The degree of prolongation in APD90 (ΔAPD90=15.5 ms) was rather small compared with the results (ΔAPD90=22.0 msec) in (A).
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Figure 7: Computer simulation of the changes in AP shape by altered properties of hERG, INa and ICaL channels. (A) Changes in AP shape by applying the altered inactivation of hERG (Fig. 6) and the decrease in Na+-channel density (75% of control) to the computational model. By this modification, the APD90 of reconstructed action potential was prolonged from 208.7 to 230.7 msec, and the peak amplitude of phase 0 was decreased, similar with the results from Fig. 1. (B) When the conductance of ICaL was reduced (80% of control) in addition to the above changes in hERG and INa, the plateau potential was also affected reproducing the results from the cardiac Purkinje fiber of rabbits. The degree of prolongation in APD90 (ΔAPD90=15.5 ms) was rather small compared with the results (ΔAPD90=22.0 msec) in (A).

Mentions: As we applied these changes in parameters (i.e. the shift of voltage-dependence of opening and closing rate constants of hERG) to the computational model of AP, it was found that APD90 was prolonged similar to the recording of APs (Fig. 7A). In Fig. 7A, the peak amplitude of AP and Vmax were also slightly decreased because the conductance of Na+ current was decreased by 25% reflecting the recorded decrease of INa. In the simulated result of Fig. 7A, however, the slight decrease of plateau level shown in Fig. 1A was not reproduced. The disparity was further resolved by considering the effect of KIOM-79 on the amplitude of ICaL. As we additionally reduced the conductance of ICaL to 85% of control, the plateau of reconstituted AP (Fig. 7B) was found to be lowered similar to that shown in Fig. 1A. The degree of prolongation in APD, however, became slightly smaller than the simulated result in Fig. 7A.


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 changes in AP shape by altered properties of hERG, INa and ICaL channels. (A) Changes in AP shape by applying the altered inactivation of hERG (Fig. 6) and the decrease in Na+-channel density (75% of control) to the computational model. By this modification, the APD90 of reconstructed action potential was prolonged from 208.7 to 230.7 msec, and the peak amplitude of phase 0 was decreased, similar with the results from Fig. 1. (B) When the conductance of ICaL was reduced (80% of control) in addition to the above changes in hERG and INa, the plateau potential was also affected reproducing the results from the cardiac Purkinje fiber of rabbits. The degree of prolongation in APD90 (ΔAPD90=15.5 ms) was rather small compared with the results (ΔAPD90=22.0 msec) in (A).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Computer simulation of the changes in AP shape by altered properties of hERG, INa and ICaL channels. (A) Changes in AP shape by applying the altered inactivation of hERG (Fig. 6) and the decrease in Na+-channel density (75% of control) to the computational model. By this modification, the APD90 of reconstructed action potential was prolonged from 208.7 to 230.7 msec, and the peak amplitude of phase 0 was decreased, similar with the results from Fig. 1. (B) When the conductance of ICaL was reduced (80% of control) in addition to the above changes in hERG and INa, the plateau potential was also affected reproducing the results from the cardiac Purkinje fiber of rabbits. The degree of prolongation in APD90 (ΔAPD90=15.5 ms) was rather small compared with the results (ΔAPD90=22.0 msec) in (A).
Mentions: As we applied these changes in parameters (i.e. the shift of voltage-dependence of opening and closing rate constants of hERG) to the computational model of AP, it was found that APD90 was prolonged similar to the recording of APs (Fig. 7A). In Fig. 7A, the peak amplitude of AP and Vmax were also slightly decreased because the conductance of Na+ current was decreased by 25% reflecting the recorded decrease of INa. In the simulated result of Fig. 7A, however, the slight decrease of plateau level shown in Fig. 1A was not reproduced. The disparity was further resolved by considering the effect of KIOM-79 on the amplitude of ICaL. As we additionally reduced the conductance of ICaL to 85% of control, the plateau of reconstituted AP (Fig. 7B) was found to be lowered similar to that shown in Fig. 1A. The degree of prolongation in APD, however, became slightly smaller than the simulated result in Fig. 7A.

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