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

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 (Vmax) and plateau potential while slightly increased the duration of action potential (APD). Consistent with the decreased Vmax and plateau potential, the peak amplitude of Na+ current (INa) and Ca2+ current (ICa,L) were decreased by KIOM-79. KIOM-79 showed dual effects on hERG K+ current; increase of depolarization phase current (Idepol) and decreased tail current at repolarization phase (Itail). The increase of APD was suspected due to the decreased Itail. 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.

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

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 (Vmax) and plateau potential while slightly increased the duration of action potential (APD). Consistent with the decreased Vmax and plateau potential, the peak amplitude of Na+ current (INa) and Ca2+ current (ICa,L) were decreased by KIOM-79. KIOM-79 showed dual effects on hERG K+ current; increase of depolarization phase current (Idepol) and decreased tail current at repolarization phase (Itail). The increase of APD was suspected due to the decreased Itail. 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.

Efectos de la adenosina sobre el automatismo y las oscilaciones post-potencial en fibras de Purkinje de mamífero / The effects of adenosine on automacity and after potential oscillations on canine cardiac Purkinje fibers

Se estudiaron los efectos de la adenosina (ADO) sobre el automatismo y las oscilaciones post-potencial de fibras de Purkinje de corazones de perro. Se emplearon concentraciones de ADO desde 10-8 hasta 10-5 M. Se obtuvieron registros de la actividad eléctrica celular mediante microelectrodos. La ADO en concentraciones mayores de 10-8 M produce durante los dos primeros minutos un incremento súbito de la longitud del ciclo básico (LCB), de alrededor del 50 por ciento de su valor control, lo que después progresa hacia un estado estable. La curva dosis-respuesta en la fase estable es sigmoidal típica y semeja a las curvas de ocupación de receptores. Las pendientes del potencial de marcadores tienden a disminuir junto con la depresión de la LCB. Las oscilaciones post-potencial inducidas por tener de estimulación muestran que la pendiente de despolarización de la oscilación post-potencial disminuye con ADO 10-8 M pero no con concentraciones mayores. Los resultados encontrados sugieren que la ADO provoca un incremento en la corriente de potasio tiempo independiente. Este efecto parece depender de la estimulación de receptores específicos. El que la adenosina tenga un curso temporal bifásico sugiere la existencia de receptores purinérgicos con afinidades y constantes de disociación distinta pero con efectos similares y que podrían ser subtipos de receptores A1

Hypertonic saline reverses bupivacaine-induced depression of rabbit Purkinje fiber depolarization Vmax

The present study describes the effect of a hypertonic increase in sodium chloride concentration on electrophysiological parameters. Membrane depolarization was recorded from rabbit Purkinje fibers superfused with warm, aerated Tyrode solution. An amount of 5% NaCl above that in normal Tyrode solution (HyNaCl, 344 mOsm) was added to the bathing medium for 30 min, significantly increasing the maximal rate of depolarization (Vmax + 15% vs - 7% for control), with minor effects on other parameters. When bupivacaine was superfused over the preparation for 30 min either in normal Tyrode or in HyNaCl, Vmax was significantly deveased (33% and 15%, respectively). HyNaCl protected the cardiac tissues from the depressive effect of 05micron/ml bupivacaine. We suggest that the infusion of hypertonic saline in intact animals may prove effective in preventing or reversing the cardiodepressant effect of bupivacaine

Efeitos do sotalol na atividade elétrica de fibras de Purkinje / Sotalol effects in electric activity of Purkinje fibers

Os efeitos eletrofisiológicos do sotalol, um bloqueador beta-adrenérgico, foram estudados em fibras de Purkinje do miocárdio de cäo, sendo utilizadas tanto preparaçöes com potencial de repouso (PR) normal (PR > -85 mV), como despolarizadeas "in vitro" pela elevaçäo do K+ na soluçäo de perfusäo (PR entre -64 e 78 mV). Os resultados mostraram que o sotalol (1 a 100 micronM) näo deprime a fase de despolarizaçäo rápida do potencial de açäo (PA), uma vez que a amplitude do PA e o valor de Vmax mantiveram-se constantes, mesmo quando as preparaçöes despolarizadas eram estimuladas com freqüências elevadas (3 a 4 Hz). O sotalol produziu um aumento dose-dependente da duraçäo do PA, o que acentuou-se em baixas freqüências de estimulaçäo. O aumento percentual na duraçäo do PA foi similar nas prepaçöes controles e despolarizadas. O período refratário efetivo aumentou na mesma proporçäo que a duraçäo do PA. A resposta lenta isolada, produzida em soluçäo de Tyrode com alto K+ + bário (1 mM), näo foi afetada em presença do sotalol. Tais dados mostram que o efeito antiarrítmico da classe III do sotalol também ocorre no miocárdio despolarizado, e é similar aquele observado nas fibras com PA normal