Potential Antiarrhythmic Effect of Methyl 3,4,5-Trimethoxycinnamate, a Bioactive Substance from Roots of <i>Polygalae Radix</i>: Suppression of Triggered Activities in Rabbit Myocytes

Abstract

3,4,5-Trimethoxycinnamic acid (TMCA), methyl 3,4,5-trimethoxycinnamate (M-TMCA) and p-methoxycinnamic acid (PMCA) have been identified as the major bioactive components in the serum collected from rats treated with oral administration of Polygalae Radix ("YuanZhi," the roots of Polygala tenuifolia Willd.), a traditional Chinese medicine used to relieve insomnia, anxiety and heart palpitation. The present study was designed to investigate its direct electrophysiological effects on isolated ventricular myocytes from rabbits. Whole-cell configuration of the patch-clamp technique was used to measure action potential (AP) and membrane currents in single ventricular myocytes enzymatically isolated from adult rabbit hearts. Ca 2+ transients were recorded in myocytes loaded with the Ca 2+ indicator Fluo-4AM. Among three bioactive substances of Polygala metabolites, only M-TMCA (15-30 µm) significantly shortened action potential duration at 50% and 90% repolarization (APD 50 and APD 90 ) in cardiomyocytes in a concentration-dependent and a reversible manner. M-TMCA also inhibited L-type calcium current (I Ca,L ), but showed effect on neither transient outward potassium current (I to ) nor steady-state potassium current (I K,SS ). Furthermore, M-TMCA abolished isoprenaline plus BayK8644-induced early afterdepolarizations (EADs) and suppressed delayed afterdepolarizations (DADs) and triggered activities (TAs). This potential anti-arrhythmic effects were likely attributed by the inhibition of I Ca,L and the suppression of intracellular Ca 2+ transients, which consequently suppress the generation of transient inward current (I ti ). These findings suggest that M-TMCA may protect the heart from arrhythmias via its inhibitory effect on calcium channel.

Antiarrhythmic Mechanisms of Chinese Herbal Medicine Dingji Fumai Decoction

“…Inflammation and oxidative stress are closely related to arrhythmia [46][47][48]. Moreover, Radix Polygalae plays an antiarrhythmic role by inhibiting the triggered activities in cardiomyocytes [45]. All of these findings suggest the antiarrhythmic mechanisms of DFD.…”

“…In addition, with the development of mass spectrometry, multiple constituents of the components of DFD have been analyzed and characterized in recent years [29][30][31][32][33][34]. Modern pharmacological studies have shown that the components of DFD have anti-inflammatory [35][36][37][38][39], antioxidative stress [40][41][42], and myocardial protection [42][43][44][45] effects. Inflammation and oxidative stress are closely related to arrhythmia [46][47][48].…”

Onjisaponin B Derived from Radix Polygalae Enhances Autophagy and Accelerates the Degradation of Mutant α-Synuclein and Huntingtin in PC-12 Cells

“…Through screening of our library of natural product extracts from Chinese medicinal herbs, it was demonstrated that both Radix Polygalae and its single component, onjisaponin B, are able to induce autophagy with potential therapeutic application in modulating neurodegeneration. With a long history of use in traditional Chinese medicine to relieve insomnia, anxiety and heart palpitation [33], Radix Polygalae and its active components were proved to be capable of improving learning and memory of aged mice [34,35], attenuating hepatic ischemia-reperfusion induced cognitive dysfunction [36], inhibiting toxin-induced neuronal death in the Parkinson’s disease models [37], as well as having cerebral protective and cognition-improving effects [38]. Therefore, the study of the neuro-protective mechanisms and therapeutic applications of Radix Polygalae and its active components would be important for novel drug discovery.…”

Research progress in the biological activities of 3,4,5-trimethoxycinnamic acid (TMCA) derivatives

“…In 2013, Zhao et al [29] presented that one of the major metabolite of P. tenuifolia in rat, 3,4,5-trimethoxycinnamate (N6), at the dosage of 15e30 mM markedly shortened APD50 (action potential duration at 50% repolarization) and APD90 (action potential duration at 90% repolarization) in cardiomyocytes in a concentrationdependent and a reversible manner ( Fig. 4).…”