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Abstract
To study the effects of berberine on inward rectifier potassium current (IK1) and outward delayed rectifier potassium current (IK) of guinea pig ventricular myocytes, and on human ether-a-go-go related gene (HERG) channel expressed in Xenopus oocytes.
Whole cell patch-clamp and geneclamp techniques were used to record ionic currents.
Berberine prolonged action potential duration (APD) and inhibited IK1 and IK in a concentration-dependent manner. Berberine 100 micromol/L increased APD90 from (450 +\- 48) ms to (888 +\- 90) ms (n = 6, P < 0.01), and inhibited IK1 by 65 % +\- 7 % (n = 6, P < 0.01). Berberine 50 micromol/L inhibited IK by 57 % +\- 6 %, IKtail by 53 % +\- 6 % (n = 6, P < 0.01). Berberine produced a voltage-dependent block on IK that increased with stronger depolarization, and once all channels were activated, there was no further block at positive potentials. Berberine blocked the HERG channels potently with an IC50 value of approximately 75 micromol/L. This block was voltage-dependent, suggesting that it probably bind to either open or inactivated HERG channels.
Berberine prolonged APD and possessed blocking effect on IK1, IK, and HERG channel expressed in Xenopus oocytes. The antiarrhythmic mechanism of berberine is related to its inhibitory effects on IK1, IK, and HERG channel.
... Main activity was identified in microfractions 24 and 25 (peak tail hERG current inhibition by 63.3 ± 16.7 % [n = 2] and 59.5 ± 20.9 % [n = 2], respectively) which corresponded to the dominant HPLC peak. With the aid of on-line (LC-PDA-MS) and off-line (1 mm microprobe NMR of collected peak) spectroscopic data, the main peak was identified as berberine (4) (l " Fig. 3), a previously reported hERG channel blocker of natural origin [18,19]. However, inhibition of the hERG current by 100 µM of a reference sample of berberine was, in our hands, less pronounced than previously reported (16.3 ± 1.6 %, n = 3, but see [18,19]). ...
... With the aid of on-line (LC-PDA-MS) and off-line (1 mm microprobe NMR of collected peak) spectroscopic data, the main peak was identified as berberine (4) (l " Fig. 3), a previously reported hERG channel blocker of natural origin [18,19]. However, inhibition of the hERG current by 100 µM of a reference sample of berberine was, in our hands, less pronounced than previously reported (16.3 ± 1.6 %, n = 3, but see [18,19]). However, subsequent LC-PDA-MS analysis showed that berberine (4) collected by microfractionation of the Coptis extract had been, in part, transformed to active dihydroberberine (6). ...
... Although berberine prolongs the action potential duration, the underlying molecular mechanism remains elusive [23]. The less pronounced hERG inhibition by berberine, in our hands, may be explained by reduced channel inhibition during the shorter conditioning pre-pulses applied in our study (300 ms vs. 4 s in [18,19]). Future studies will show if the different voltage protocols applied induce different state-dependent hERG inhibition [17]. ...
Inhibition of the hERG channel delays repolarization and prolongs the QT interval and cardiac action potential which can lead to sudden death. Several drugs have been withdrawn from the market due to hERG channel inhibition. In the search of hERG channel inhibitors of natural origin, we established an HPLC-based profiling approach which combines HPLC-microfractionation and bioactivity testing on Xenopus laevis oocytes. The methanolic extract of the TCM herbal drug Coptidis rhizoma (Coptis chinensis Franch., Ranunculaceae) reduced the peak tail hERG current by 31.7 ± 2.0% at 100 µg/mL. HPLC-based activity profiling pointed towards berberine as the active constituent. However, hERG inhibition by 100 µM of a reference sample of berberine (16.3 ± 1.6%) was less pronounced than previously reported. Subsequent LC-PDA-MS analysis showed that berberine collected by microfractionation of the Coptis extract had been, in part, transformed to active dihydroberberine. Formic acid added to the HPLC mobile phase to reduce peak tailing of protoberberine alkaloids acted as a reducing reagent according to the mechanism of the Leuckart-Wallach reaction. Among other structurally related protoberberines tested, dihydroberberine (30.1 ± 10.1% at 100 µM) was the most potent hERG inhibitor.
... Berberine, a class of isoquinoline alkaloids, is considered to be the major risk substance in various CMM, such as Coptis chinensis and Cortex Phellodendri Chinensis. It has been reported that berberine acutely inhibits human ether-a-gogo-related gene (hERG) currents and prolongs action potential duration in Xenopus oocytes (Li et al., 2001). Studies in vivo showed that high concentrations of alkaloids, including berberine, coptisine, palmatine, and jatrorrhizine, were found in heart tissues of mice. ...
... Some toxic CMM induce cardiotoxicity by directly inhibiting the expression of hERG channel protein or coding gene to suppress potassium channels. For instance, berberine blocked I k1 , I k , and hERG channels expressed in Xenopus oocytes (Li et al., 2001). Diterpene alkaloids, such as aconitine and hypaconitine, induced QT interval prolongation through the inhibition of hERG potassium channels Xie et al., 2015;Kiss et al., 2017). ...
Chinese materia medica (CMM) has been applied for the prevention and treatment of diseases for thousands of years. However, arrhythmia, myocardial ischemia, heart failure, and other cardiac adverse reactions during CMM application were gradually reported. CMM-induced cardiotoxicity has aroused widespread attention. Our review aimed to summarize the risk compounds, preclinical toxicity evaluation, and potential mechanisms of CMM-induced cardiotoxicity. All relevant articles published on the PubMed, Embase, and China National Knowledge Infrastructure (CNKI) databases for the latest twenty years were searched and manually extracted. The risk substances of CMM-induced cardiotoxicity are relatively complex. A single CMM usually contains various risk compounds, and the same risk substance may exist in various CMM. The active and risk substances in CMM may be transformed into each other under different conditions, such as drug dosage, medication methods, and body status. Generally, the risk compounds of CMM-induced cardiotoxicity can be classified into alkaloids, terpenoids, steroids, heavy metals, organic acids, toxic proteins, and peptides. Traditional evaluation methods of chemical drug-induced cardiotoxicity primarily include cardiac function monitoring, endomyocardial biopsy, myocardial zymogram, and biomarker determination. In the preclinical stage, CMM-induced cardiotoxicity should be systematically evaluated at the overall, tissue, cellular, and molecular levels, including cardiac function, histopathology, cytology, myocardial zymogram, and biomarkers. Thanks to the development of systematic biology, the higher specificity and sensitivity of biomarkers, such as genes, proteins, and metabolic small molecules, are gradually applied for evaluating CMM-induced cardiotoxicity. Previous studies on the mechanisms of CMM-induced cardiotoxicity focused on a single drug, monomer or components of CMM. The interaction among ion homeostasis (sodium, potassium, and calcium ions), oxidative damage, mitochondrial injury, apoptosis and autophagy, and metabolic disturbance is involved in CMM-induced cardiotoxicity. Clarification on the risk compounds, preclinical toxicity evaluation, and potential mechanisms of CMM-induced cardiotoxicity must be beneficial to guide new CMM development and post-marketed CMM reevaluation.
... Therefore, DHB is considered a potential candidate agent for the development of new drugs and would likely be even more promising than BBR is. It has been confirmed that BBR could block the hERG channel and prolong action potential duration (APD) [14,15]. Importantly, the combination of BBR with antibiotics enhances the inhibitory effects on the hERG channel [16]. ...
... Since previous studies have demonstrated that BBR inhibits both hERG current and the expression of hERG protein [14,15], in this study, we aimed to investigate the potential inhibition of the current and protein of the hERG channel by DHB in HEK293 cells stably expressing the wild-type (WT) hERG. Moreover, HEK293 cells transiently transfected with hERG cDNA was used to determine the sites of hERG channel that were bound by DHB. ...
The human ether-a-go-go-related gene (hERG) potassium channel conducts rapid delayed rectifier potassium currents (IKr) and contributes to phase III cardiac action potential repolarization. Drugs inhibit hERG channels by binding to aromatic residues in hERG helixes. Berberine (BBR) has multiple actions, and its hydrogenated derivative dihydroberberine (DHB) is a potential candidate for developing new drugs. Previous studies have demonstrated that BBR blocks hERG channels and prolongs action potential duration (APD). Our present study aimed to investigate the effects and mechanism of DHB on hERG channels. Protein expression and the hERG current were analyzed using western blotting and patch-clamp, respectively. DHB inhibited the hERG current concentration-dependently after instantaneous perfusion, accelerated channel inactivation by directly binding tyrosine (Tyr652) and phenylalanine (Phe656), and decreased mature (155-kDa) and simultaneously increased immature (135-kDa) hERG expression, respectively. This suggests disruption of forward trafficking of hERG channels. Besides, DHB remarkably reduced heat shock protein 90 (Hsp90) expression and its interaction with hERG, indicating that DHB disrupted hERG trafficking by impairing channel folding. Meanwhie, DHB enhanced the expression of cleaved activating transcription factor-6 (ATF-6), a biomarker of unfolded protein response (UPR). Expression of calnexin and calreticulin, chaperones activated by ATF-6 to facilitate channel folding, were also increased, which indicating UPR activation. Additionally, the degradation rate of mature 155-kDa hERG increased following DHB exposure. In conclusion, we demonstrated that DHB acutely blocked hERG channels by binding the aromatic Tyr652 and Phe656. DHB may decrease hERG plasma membrane expression through two pathways involving disruption of forward trafficking of immature hERG channels and enhanced degradation of mature hERG channels. Furthermore, forward trafficking was disrupted by impaired channel folding associated with altered interactions between hERG proteins and chaperones. Finally, trafficking inhibition activated UPR, and mature hERG channel degradation was increased by DHB.
... Berberine has been suggested to act as a class IA or III antiarrhythmic agent. In vitro studies reported different possible mechanisms for the observed effects of berberine, such as K + channels blockade (32,33), decreasing Na + influx (30), and increase of [Ca +2 ]i (34). Berberine can indirectly supplement anti-arrhythmic drugs by its inhibitory effect on the human CYP3A4 enzyme, through which many of these drugs are metabolized, increasing their potency. ...
... In a clinical study by Zeng and Li, in patients with congestive heart failure (CHF), berberine reduced the frequency of ventricular premature complexes and increased the left ventricular ejection fraction (EF) (36). Other pharmacological studies have shown that it can prevent the development of ventricular fibrillation (VF) due to its inhibitory effect on K + channels (32,33). Although berberine has not been tested in large-scale clinical studies, the existing body of literature shows a great potential for this compound as a future anti-arrhythmic drug. ...
Objective(s): Cardiovascular disorders are the leading cause of mortality worldwide. Berberis vulgaris (B. vulgaris) is a commonly used plant in traditional medicine. In recent studies, B. vulgaris showed antiarrhythmic, antihypertensive, anticholinergic, and cardioprotective effects. We reviewed the literature to explore the possible prophylactic and therapeutic roles of B. vulgaris in cardiovascular medicine. A computer literature search was conducted to identify all relevant studies that have investigated the role of B. vulgaris in prevention or treatment of cardiovascular diseases. We also searched the citations of the retrieved articles. Using a systematic approach, we conducted a scoping review that included a total of 37 articles. Twelve studies examined the antihypertensive effects of B. vulgaris, seven studies investigated its antiarrhythmic effects, while its inotropic and cardioprotective effects were evaluated in four and eight studies, respectively. B. vulgaris showed a beneficial effect in reducing blood pressure, enhancing cardiac contractility, and protection from reperfusion injury. However, the mechanisms of these effects are still under investigation. Moreover, it could modify major risk factors for cardiovascular disorders, such as oxidative stress, hyperglycemia, and hyperlipidemia. Further studies are needed to translate these findings into effective cardiovascular medications. © 2017, Mashhad University of Medical Sciences. All rights reserved.
... Myocytes were patch-clamped in the whole-cell configuration as previously described [11]. Voltage or current signals were obtained with a MultiClamp 700B patch-clamp amplifier using a Digidata 1440 acquisition board driven by pCLAMP 10 software (Molecular Devices, Sunnyvale, CA) and stored on a computer for analysis. ...
... Several laboratories have shown that Ber possesses anti-arrhythmic actions through the prolongation of APD [11] as a result of blocking several ion channels, including K + channels. Sanchez-Chapula [12] showed that Ber could prolong APD by blocking I Kr at concentrations of 0.3-30 µM. ...
The purpose of this study was to test the efficacy of Berberine (Ber) on atrial fibrillation (AF) induced by acetylcholine (ACh) and explore its underlying mechanisms of action. In vivo electrophysiology experiments were performed in adult anesthetized rabbits. Single atrial myocytes were isolated from rabbit hearts and action potentials recorded using patch clamp techniques. AF was induced by rapid atrial burst pacing during intravenous (IV) ACh infusion alone or with IV Ber. Compared to the Baseline, IV Ber (2 mg/kg) prolonged the RR interval and effective refractory period (195 ± 10 vs. 215 ± 11 msec; 80 ± 4 vs. 85 ± 5 msec, respectively; both P<0.05). The induced rate of sustained 1 min AF was lower during ACh infusion with Ber than during ACh infusion alone (4/10 vs. 30/35, P<0.01). The termination rate of ACh-induced AF was higher with IV Ber (1 mg/kg) than with IV saline (sustained 1 min AF: 6/8 vs. 6/20, sustained 10 min AF: 8/10 vs. 1/6, both P<0.05). ACh perfusion significantly shortened the action potential duration (APD) of isolated atrial myocytes (APD50: 152 ± 13 vs. 81 ± 10 msec; APD90: 256 ± 19 vs. 132 ± 13 msec, both P<0.01). Application of Ber reversed the APD shortening induced by ACh (APD50: 81 ± 10 vs. 134 ± 15 msec; APD90: 132 ± 13 vs: 213 ± 17 msec, both P<0.01). We conclude that Ber suppresses ACh-induced AF in the rabbit by increasing atrial effective refractory period and prolonging the APD of atrial myocytes.
... Berberine (BBR) is an isoquinoline alkaloid that is used clinically to treat bacillary diarrhea and to lower lipids along with simvastatin [7]. Previous studies reported that BBR acutely blocks the hERG channel and prolongs action potential duration (APD) in Xenopus oocytes [8]. We recently found that long-term incubation of BBR reduces expression of the hERG protein in rat ventricular tissue [9]; however, the mechanism is still unknown. ...
... In fact, previous studies showed that BBR acutely blocks both L-and T-type calcium channels [24]. In addition, BBR has been shown to inhibit Iks and Ik1 [8,25]. Because Ica, Ikr, Iks and Ik1 are the main currents responsible for the repolarization of action potentials, we conclude that the prolonged APD caused by BBR incubation is due to combined effects on various currents. ...
Aims:
The human ether-a-go-go-related gene (hERG) encodes the α subunit of the IKr, which plays an essential role in repolarization of action potentials. hERG channels are targeted by various pro-arrhythmic drugs. Berberine (BBR) was previously found to acutely inhibit hERG currents and prolong action potential duration. The present study aimed to determine long-term effects of BBR on the expression of 135kDa/155kDa hERG and the mechanism.
Methods and results:
hERG expression was assessed by western blot. Mature hERG (155 kDa) was reduced, whereas ER-located hERG (135 kDa) was increased by BBR. This indicated that hERG was restricted to the ER and that BBR disrupted channel trafficking. To determine the mechanism of trafficking inhibition, we performed western blot and immunoprecipitation to test folding of hERG by assessing interaction between hERG and Hsp90/Hsp70. Both the expression of Hsp90 and its interaction with hERG were strongly decreased by BBR. These data suggest that BBR reduces channel folding to induce trafficking inhibition. Western blot and confocal imaging were used to further detect whether the unfolded protein response (UPR) was activated. Active ATF6, a marker of the UPR, was activated by BBR. Calnexin and calreticulin, chaperones that are activated by ATF6 to assist channel folding, were also elevated and increasingly colocalized with hERG. These data also demonstrate that the UPR was activated. Immunoprecipitation and western blot assays were performed after BBR treatment to examine ubiquitination and degradation, common endpoints of the UPR. We found that the ER-restricted hERG was ubiquitinized and degraded in the lysosomes and proteasomes.
Conclusion:
Our study demonstrates that BBR induces hERG channel deficiency by inhibiting channel trafficking after incubation for 24h. Trafficking inhibition activated the UPR, and the ER-restricted hERG was ubiquitinized and degraded in lysosomes and proteasomes.
... Potassium channels play an important role in stimulating the heart and usually serve as a target in determining the effect of antiarrhythmic compounds, and prevent QTc from rising, which results in arrhythmia and death (33,34). Therefore, development of antiarrhythmic therapeutics for reducing QTc has been one of the main goals of many studies. ...
... This effect can be likened to the action of subclass IIIb AADs, specifically inward rectifier K + current (I K 1 ) agonists, which speeds up the late phase 3 AP repolarization and stabilizes phase 4 diastolic resting potentials (7). Some mechanistic studies further studied the pharmacological targets and electrophysiological effects of berberine on isolated cardiac myocytes and found its inhibitory effects on I K 1 , slow delayed rectifier K + current (I Ks ), and I K r , which subsequently could prolong the repolarization phase of AP duration and ERP, similar to the action of subclass IIIa AADs (54)(55)(56). However, these studies have been designed in non-pathologic conditions, so further studies are needed to assess these mechanisms alongside the outcomes related to arrhythmias. ...
Cardiac arrhythmias, characterized by an irregular heartbeat, are associated with high mortality and morbidity. Because of the narrow therapeutic window of antiarrhythmic drugs (AADs), the management of arrhythmia is still challenging. Therefore, searching for new safe, and effective therapeutic options is unavoidable. In this study, the antiarrhythmic effects of medicinal plants and their active constituents were systematically reviewed to introduce some possible candidates for mechanism-based targeting of cardiac arrhythmias. PubMed, Embase, and Cochrane library were searched from inception to June 2021 to find the plant extracts, phytochemicals, and multi-component herbal preparations with antiarrhythmic activities. From 7337 identified results, 57 original studies consisting of 49 preclinical and eight clinical studies were finally included. Three plant extracts, eight multi-component herbal preparations, and 26 phytochemicals were found to have antiarrhythmic effects mostly mediated by affecting K+ channels, followed by modulating Ca2+ channels, upstream target pathways, Nav channels, gap junction channels, and autonomic receptors. The most investigated medicinal plants were Rhodiola crenulata and Vitis vinifera. Resveratrol, Oxymatrine, and Curcumin were the most studied phytochemicals found to have multiple mechanisms of antiarrhythmic action. This review emphasized the importance of research on the cardioprotective effect of medicinal plants and their bioactive compounds to guide the future development of new AADs. The most prevalent limitation of the studies was their unqualified methodology. Thus, future well-designed experimental and clinical studies are necessary to provide more reliable evidence.
... Berberine also shows the 420 inhibitory effect with K + and Ca + for the selected rat hepatocytes and has 421 hepatoprotective function (Wang et al. 1991, Janbaz and Gilani 2000. The cardiovascular effects of berberine was mentioned in several studies carried out 424 across the globe (Shaffer 1985, Eaker andSninsky 1989;Xu et al. 1989;Huang et al. 425 1989, Huang 1990a, Wang et al. 1991, Riccioppo 1993, Zhou et al. 1993, Hua and 426 Wang 1994, Wang and Zheng 1997Zeng 1999;Liu et al. 1999, 427 Zhou et al. 2001, Li et al. 2001, Hong et al. 2003 Doggrell 2005, Brusq et al. 2006429 Chang et al. 2016;Chopra aand Vishwakarma 2018) and reported Inoue et al. (2005) were of the opinion that berberine when tested in vivo to B16 cell 473 lines with a dose ranging from 1 to 10 mg/kg stimulates tumour mass at the lower 474 dose of 1 mg/kg, whereas berberine dose of 5 and 10 mg/kg reduced the overall 475 tumour weight. Chen et al. (1994) found that berberine inhibits the nitrogen-476 acetyltransferase function in HCT cells with respect to the dose-dependent manner 477 leading to cell death, which means that at maximum berberine concentration, 478 nitrogen-acetyltransferase and cell death inhibition were higher. ...
Alkaloid berberine is chemically represented as quaternary nitrogen structure, first isolated from Xanthoxylon cava Wall. long ago in the eighteenth century. Currently, this alkaloid is regarded as the most bioactive compound used by pharma industries for research and development of drugs and herbal formulations, since it is extensively employed for hundreds of years in curing numerous infectious diseases and in traditional Ayurvedic and Chinese medicine for curing diarrhoea and as a detoxifying agent. Since long time, this compound is detected, isolated, and quantified from different families of plants such as Annonaceae (e.g. Xylopia L.), Berberidaceae (e.g. Berberis L.), Menispermaceae (e.g. Tinospora Miers), Papaveraceae (e.g. Argemone L.), Ranunculaceae (e.g. Coptis Salisb.) and Rutaceae (e.g. Zanthoxylum L.), and most of these plants are growing in high-altitude regions of the Himalaya. Reported studies indicate that berberine possesses several pharmacological activities and cure inflammation, diabetes, cancer etc., thereby multiple of mechanisms, as the case may be halting cycle of the cell progression or triggers apoptosis. This chemical constituent shows significant activities such as antimicrobial (bacterial, fungal, protozoans, viral, helminthes), antidiarrhoeal, antitumor and apoptosis, anticarcinogenic, immunomodulatory, antihyperglycaemic, antioxidant, hepatoprotective, cardiovascular and several miscellaneous biological functions associated with human healthcare. This communication reviews and provided various undated information on the botanical sources, berberine extraction techniques and quantification methods, chemistry and several biological functions coupled with different clinical studies undertaken associated with berberine and allied research. This one place data will serve as future baseline data for researchers interested to work more on berberine and pharma industry for medicine development.
... Berberine also shows the 420 inhibitory effect with K + and Ca + for the selected rat hepatocytes and has 421 hepatoprotective function (Wang et al. 1991, Janbaz and Gilani 2000. The cardiovascular effects of berberine was mentioned in several studies carried out 424 across the globe (Shaffer 1985, Eaker andSninsky 1989;Xu et al. 1989;Huang et al. 425 1989, Huang 1990a, Wang et al. 1991, Riccioppo 1993, Zhou et al. 1993, Hua and 426 Wang 1994, Wang and Zheng 1997Zeng 1999;Liu et al. 1999, 427 Zhou et al. 2001, Li et al. 2001, Hong et al. 2003 Doggrell 2005, Brusq et al. 2006429 Chang et al. 2016;Chopra aand Vishwakarma 2018) and reported Inoue et al. (2005) were of the opinion that berberine when tested in vivo to B16 cell 473 lines with a dose ranging from 1 to 10 mg/kg stimulates tumour mass at the lower 474 dose of 1 mg/kg, whereas berberine dose of 5 and 10 mg/kg reduced the overall 475 tumour weight. Chen et al. (1994) found that berberine inhibits the nitrogen-476 acetyltransferase function in HCT cells with respect to the dose-dependent manner 477 leading to cell death, which means that at maximum berberine concentration, 478 nitrogen-acetyltransferase and cell death inhibition were higher. ...
Alkaloid berberine is chemically represented as quaternary nitrogen structure, first isolated from Xanthoxylon cava Wall. long ago in the eighteenth century. Currently, this alkaloid is regarded as the most bioactive compound used by pharma industries for research and development of drugs and herbal formulations, since it is extensively employed for hundreds of years in curing numerous infectious diseases and in traditional Ayurvedic and Chinese medicine for curing diarrhoea and as a detoxifying agent. Since long time, this compound is detected, isolated, and quantified from different families of plants such as Annonaceae (e.g. Xylopia L.), Berberidaceae (e.g. Berberis L.), Menispermaceae (e.g. Tinospora Miers), Papaveraceae (e.g. Argemone L.), Ranunculaceae (e.g. Coptis Salisb.) and Rutaceae (e.g. Zanthoxylum L.), and most of these plants are growing in high-altitude regions of the Himalaya. Reported studies indicate that berberine possesses several pharmacological activities and cure inflammation, diabetes, cancer etc., thereby multiple of mechanisms, as the case may be halting cycle of the cell progression or triggers apoptosis. This chemical constituent shows significant activities such as antimicrobial (bacterial, fungal, protozoans, viral, helminthes), antidiarrhoeal, antitumor and apoptosis, anticarcinogenic, immunomodulatory, antihyperglycaemic, antioxidant, hepatoprotective, cardiovascular and several miscellaneous biological functions associated with human healthcare. This communication reviews and provided various undated information on the botanical sources, berberine extraction techniques and quantification methods, chemistry and several biological functions coupled with different clinical studies undertaken associated with berberine and allied research. This one place data will serve as future baseline data for researchers interested to work more on berberine and pharma industry for medicine development.
... Berberine also shows the 420 inhibitory effect with K + and Ca + for the selected rat hepatocytes and has 421 hepatoprotective function (Wang et al. 1991, Janbaz and Gilani 2000. The cardiovascular effects of berberine was mentioned in several studies carried out 424 across the globe (Shaffer 1985, Eaker andSninsky 1989;Xu et al. 1989;Huang et al. 425 1989, Huang 1990a, Wang et al. 1991, Riccioppo 1993, Zhou et al. 1993, Hua and 426 Wang 1994, Wang and Zheng 1997Zeng 1999;Liu et al. 1999, 427 Zhou et al. 2001, Li et al. 2001, Hong et al. 2003 Doggrell 2005, Brusq et al. 2006429 Chang et al. 2016;Chopra aand Vishwakarma 2018) and reported Inoue et al. (2005) were of the opinion that berberine when tested in vivo to B16 cell 473 lines with a dose ranging from 1 to 10 mg/kg stimulates tumour mass at the lower 474 dose of 1 mg/kg, whereas berberine dose of 5 and 10 mg/kg reduced the overall 475 tumour weight. Chen et al. (1994) found that berberine inhibits the nitrogen-476 acetyltransferase function in HCT cells with respect to the dose-dependent manner 477 leading to cell death, which means that at maximum berberine concentration, 478 nitrogen-acetyltransferase and cell death inhibition were higher. ...
... The cardiovascular effects of berberine was mentioned in several studies carried out across the globe (Shaffer 1985, Eaker andSninsky 1989;Huang et al. 1989, Huang 1990a, Wang et al. 1991, Riccioppo 1993, Zhou et al. 1993, Hua and Wang 1994, Li and Wang 1997, Wang and Zheng 1997Liu et al. 1999, Li et al. 2001, Hong et al. 2003, Yang et al. 2004, Abidi et al. 2005, Doggrell 2005, Brusq et al. 2006, Zhao et al. 2007Park et al. 2014;Zaha et al. 2016;Chang et al. 2016;Chopra aand Vishwakarma 2018, Neag et al. 2018 reported that the mechanism of antihypertensive effect of 6-protoberberine was through the central sympatholytic effect , Chopra aand Vishwakarma 2018. Berberine derivative 6-protoberberine is an effective antihypertensive agent . ...
Alkaloid berberine is chemically represented as quaternary nitrogen structure, first isolated from Xanthoxylon cava Wall. long ago in the eighteenth century. Currently, this alkaloid is regarded as the most bioactive compound used by pharma industries for research and development of drugs and herbal formulations, and it is extensively employed for hundreds of years in curing numerous infectious diseases and in traditional Ayurvedic and Chinese medicine for curing diarrhoea as a detoxifying agent. Since long time, this compound is detected, isolated, and quantified from different families of plants such as Annonaceae (e.g. Xylopia L.), Berberidaceae (e.g. Berberis L.), Menispermaceae (e.g. Tinospora Miers), Papaveraceae (e.g. Argemone L.), Ranunculaceae (e.g. Coptis Salisb.) and Rutaceae (e.g. Zanthoxylum L.); most of these plants are growing in high-altitude regions of the Himalaya. Reported studies indicate that berberine possesses several pharmacological activities and cure inflammation, diabetes, cancer etc., thereby multiple of mechanisms, as the case may be halting cycle of the cell progression or triggers apoptosis. This chemical constituent shows significant activities such as antimicrobial (bacterial, fungal, protozoans, viral, helminthes), antidiarrhoeal, antitumor and apoptosis, anticarcinogenic, immunomodulatory, antihyperglycaemic, antioxidant, hepatoprotective, cardiovascular and several miscellaneous biological functions associated with human healthcare. This communication reviews and provided various undated information on the botanical sources, berberine extraction techniques and quantification methods, chemistry and several biological functions coupled with different clinical studies undertaken associated with berberine and allied research. This one place data will serve as future baseline data for researchers interested to work more on berberine and pharma industry for drug discovery and medicine development
... Following assay characterization, we screened a library of 87 chemicals that included four major chemical classes with agents of known or suspected neurotoxic potential, including pesticides (Dingemans et al., 2011;Gao et al., 2002;Hassenklö ver et al., 2006;Abou-Donia 2003;Hendriks and Westerink, 2015;Jang et al., 2015;Ryan et al., 2016;Tang et al., 2003), flame retardants (Flaskos, 2012;Hassenklö ver et al., 2006;Lema et al., 2007), PAHs (Billiard et al., 2006;Burstyn et al., 2005), and drugs (Li et al., 2001) as well as compounds with unknown neurotoxic potential, and 5 negative controls. More than half of the tested compounds, 47 out of 82 (57%, excluding controls), demonstrated concentration-dependent perturbation of the calcium oscillation patterns, which we propose as a screening phenotype for neurotoxicity ( Figure 10). ...
Neurological disorders affect millions of people worldwide and appear to be on the rise. While the reason for this increase remains unknown, environmental factors are a suspected contributor. Hence, there is an urgent need to develop more complex, biologically relevant, and predictive in vitro assays to screen larger sets of compounds with the potential for neurotoxicity. Here, we employed a human induced pluripotent stem cell (iPSC)-based 3D neural platform composed of mature cortical neurons and astrocytes as a model for this purpose. The iPSC-derived human 3D cortical neuron/astrocyte co-cultures (3D neural cultures) present spontaneous synchronized, readily detectable calcium oscillations. This advanced neural platform was optimized for high-throughput screening in 384-well plates and displays highly consistent, functional performance across different wells and plates. Characterization of oscillation profiles in 3D neural cultures was performed through multi-parametric analysis that included the calcium oscillation rate and peak width, amplitude, and waveform irregularities. Cellular and mitochondrial toxicity were assessed by high-content imaging. For assay characterization, we used a set of neuromodulators with known mechanisms of action. We then explored the neurotoxic profile of a library of 87 compounds that included pharmaceutical drugs, pesticides, flame retardants, and other chemicals. Our results demonstrated that 57% of the tested compounds exhibited effects in the assay. The compounds were then ranked according to their effective concentrations based on in vitro activity. Our results show that a human iPSC-derived 3D neural culture assay platform is a promising biologically-relevant tool to assess the neurotoxic potential of drugs and environmental toxicants.
... Previous studies demonstrate that berberine (10-100 µM) can reversibly block human ether-a-go-go (hERG) channels in Xenopus oocytes (53) by directly binding to F656V (54). This inhibitory concentration was higher than the effective concentration in clinical application (53). The IC50 for berberine on hERG in HEK-293 cells and Xenopus oocytes has been reported 3.1±0.5 and 80±5 µM, respectively (55). ...
Objective(s): Berberis vulgaris and berberine, its main component, traditionally have been used for treatment of various disorders. The pharmacological properties of them have been investigated using different in vivo and in vitro models. In spite of beneficial effects of B. vulgaris on different cell lines, there are documents have revealed negative impacts of it on animal and human. In this regards, the determination of its toxicity in a scientific view is necessary. In current report, we provide classified information about the toxicity of B. vulgaris and berberine in different conditions consist of acute, subacute, sub-chronic and chronic state. Besides, it discusses the cytotoxicity, genotoxicity, mutagenicity, and carcinogenicity of B. vulgaris and berberine as well as developmental toxicity and clinical studies. Data from the present study indicate that their toxicity is depending on the route and duration of administration. According to present study, they could induce GI upset and ulceration, immunotoxicity, phototoxicity, neurotoxicity, cardiotoxicity and jaundice in a dose dependent manner. They should be used with caution in pregnancy, neonatal and G6PD deficiency. Besides, consideration should be taken in co-administration of berberine with drugs that are metabolized with CYP enzymes due their inhibitory effects on these enzymes. Furthermore, they evoke cytotoxicity on both normal and cancer cell line which is time and concentration dependent. © 2017, Mashhad University of Medical Sciences. All rights reserved.
... Following assay characterization, we screened a library of 87 chemicals that included four major chemical classes with agents of known or suspected neurotoxic potential, including pesticides (Dingemans et al., 2011;Gao et al., 2002;Hassenklö ver et al., 2006;Abou-Donia 2003;Hendriks and Westerink, 2015;Jang et al., 2015;Ryan et al., 2016;Tang et al., 2003), flame retardants (Flaskos, 2012;Hassenklö ver et al., 2006;Lema et al., 2007), PAHs (Billiard et al., 2006;Burstyn et al., 2005), and drugs (Li et al., 2001) as well as compounds with unknown neurotoxic potential, and 5 negative controls. More than half of the tested compounds, 47 out of 82 (57%, excluding controls), demonstrated concentration-dependent perturbation of the calcium oscillation patterns, which we propose as a screening phenotype for neurotoxicity ( Figure 10). ...
An important target area for addressing data gaps through in vitro screening is the detection of potential cardiotoxicants. Despite the fact that current conservative estimates relate at least 23% of all cardiovascular disease cases to environmental exposures, the identities of the causative agents remain largely uncharacterized. Here, we evaluate the feasibility of a combinatorial in vitro/in silico screening approach for functional and mechanistic cardiotoxicity profiling of environmental hazards using a library of 69 representative environmental chemicals and drugs. Human induced pluripotent stem cell-derived cardiomyocytes were exposed in concentration-response for 30 min or 24 h and effects on cardiomyocyte beating and cellular and mitochondrial toxicity were assessed by kinetic measurements of intracellular Ca2 + flux and high-content imaging using the nuclear dye Hoechst 33342, the cell viability marker Calcein AM, and the mitochondrial depolarization probe JC-10. More than half of the tested chemicals exhibited effects on cardiomyocyte beating after 30 min of exposure. In contrast, after 24 h, effects on cell beating without concomitant cytotoxicity were observed in about one third of the compounds. Concentration-response data for in vitro bioactivity phenotypes visualized using the Toxicological Prioritization Index (ToxPi) showed chemical class-specific clustering of environmental chemicals, including pesticides, flame retardants, and polycyclic aromatic hydrocarbons. For environmental chemicals with human exposure predictions, the activity-to-exposure ratios between modeled blood concentrations and in vitro bioactivity were between one and five orders of magnitude. These findings not only demonstrate that some ubiquitous environmental pollutants might have the potential at high exposure levels to alter cardiomyocyte function, but also indicate similarities in the mechanism of these effects both within and among chemicals and classes.
... Moreover, berberine is a typical multichannel ion blocker. Previous studies have showed that it can inhibit KATP [15], IKV [16], IKCa [16], IK1, and IK [17]. Regrettably, though berberine shows promising function on AF (Table 1), the advantages have not been systematically studied in human clinical trials. ...
Atrial fibrillation (AF) is the most common cardiac arrhythmia, which is related to many cardiac and cerebral vascular diseases, especially stroke. It can therefore increase cardiovascular mortality and all-cause death. The current treatments of AF remain to be western drugs and radiofrequency ablation which are limited by the tolerance of patients, adverse side effects, and high recurrence rate, especially for the elderly. On the contrary, traditional Chinese medicine (TCM) with long history of use involves various treatment methods, including Chinese herbal medicines (CHMs) or bioactive ingredients, Chinese patent medicines, acupuncture, Qigong, and Tai Chi Chuan. With more and more researches reported, the active roles of TCM in AF management have been discovered. Then it is likely that TCM would be effective preventive means and valuable additional remedy for AF. The potential mechanisms further found by numerous experimental studies showed the distinct characteristics of TCM. Some CHMs or bioactive ingredients are atrial-selective, while others are multichannel and multifunctional. Therefore, in this review we summarized the treatment strategies reported in TCM, with the purpose of providing novel ideas and directions for AF management.
... It is surprising that such a diverse categories of drugs are capable of inhibiting the hERG channel including antiarrhythmic, antipsychotic and antidepressant drugs. For example, berberine inhibits the hERG channel causing APD prolongation [53] . Arsenic trioxide prolongs the QT interval by inhibiting hERG channel expression and increasing the calcium current [7] . ...
The human ether-à-go-go related gene (hERG) potassium channel is an obligatory anti-target for drug development on account of its essential role in cardiac repolarization and its close association with arrhythmia. Diverse drugs have been removed from the market owing to their inhibitory activity on the hERG channel and their contribution to acquired long QT syndrome (LQTS). Moreover, mutations that cause hERG channel dysfunction may induce congenital LQTS. Recently, an increasing number of biochemical and molecular mechanisms underlying hERG-associated LQTS have been reported. In fact, numerous potential biochemical and molecular rescue strategies are hidden within the biogenesis and regulating network. So far, rescue strategies of hERG channel dysfunction and LQTS mainly include activators, blockers, and molecules that interfere with specific links and other mechanisms. The aim of this review is to discuss the rescue strategies based on hERG channel toxicology from the biochemical and molecular perspectives.
... L-type Ca 2+ (I Ca-L ) and the Na + -Ca 2+ exchange current (16)(17)(18)(19)(20). ...
The present study investigated the electropharmacological effects of a traditional Chinese herbal drug, berberine, on the spontaneous activity of sinoatrial nodes (SANs) of the rabbit heart and on human hyperpolarization-activated cyclic nucleotide-gated 4 (hHCN4) channels, which are heterologously expressed in xenopus oocytes, and which contribute to pacemaker currents (Ifs). A standard microelectrode technique and standard two‑electrode voltage‑clamp recordings were employed to examine the properties of transmembrane potentials and cloned hHCN4 subunit currents, respectively, under control conditions and berberine administration. Berberine decreased the rate of pacemaker firing and the rate of diastolic depolarization, and modified the action potential parameters. In addition, berberine suppressed the hHCN4 channel currents in a concentration‑ (1‑300 µM) and use‑dependent manner, and simultaneously decreased the activation and deactivation kinetics of the hHCN4 channels. The ability of berberine to modulate the If of cardiac pacemaker cells may contribute to its antiarrhythmic action.
... It has a tip resistance of megohms when filled with pipette solution containing (in mM) 130 KCl, 1 MgCl 2 , 5 Mg-ATP, 10 EGTA, and 10 HEPES (pH 7.3). Then currents were recorded using whole-cell patch-clamp with an Axopatch-200B amplifier and pCLAMP 8.0 software (Axon Instruments Inc., Union City, CA, USA) at room temperature as previously reported [37]. I k1 as a Ba 2þsensitive current was measured using 300 ms steps from À120 mV to 50 mV (10 mV increments) in the presence of holding potential and absence of 0.3 mM BaCl 2 . ...
... berberine and resveratrol possess anti-arrhythmic effects because of their inhibitory actions on hERG channels (12,13). Thus, interference with hERG channels seems to be the main mechanism explaining both therapeutic and cardiotoxic actions. ...
We investigated the effects of Ginkgo biloba extract (GBE) and ginkgolide (GLD) on human ether-a-go-go-related gene (hERG)-encoded K(+) channels and its underlying mechanisms in the hERG-HEK293 cell line by determining GBE- and GLD-induced changes in action potential duration (APD), L-type calcium currents (ICa-L), and the intracellular calcium concentration ([Ca(2+)]i) in guinea-pig ventricular myocytes. hERG currents, APD and ICa-L were recorded using the whole-cell patch clamp technique, the [Ca(2+)]i was examined by an immunofluorescence experiment. In the present study, we found that a low concentration of GBE (0.005 mg/ml) increased hERG currents, but the high concentration of GBE (from 0.05 to 0.25 mg/ml) reduced hERG currents. GLD reduced hERG currents in a concentration-dependent manner (from 0.005 to 0.25 mg/ml). Both GBE and GLD altered kinetics of the hERG channel. GBE accelerated the activation of hERG channels without changing the inactivation curve, but reduced the time constant of inactivation; GLD did not shift the activation or the inactivation curve, but only reduced the time constant of inactivation. Both GBE and GLD shortened the APD, inhibited the ICa-L currents, and decreased the [Ca(2+)]i in isolated guinea-pig ventricular myocytes. The results indicate that GBE and GLD can prevent ischemic arrhythmias and have an antiarrhythmic effect potential via inhibition of IKr and ICa-L currents.
... Berberine has multiple cardiovascular effects, including negative chronotropic, antiarrhythmic and vasodilatory properties [1,2] and an antiinflammatory effect [6] . Several cardiovascular effects of berberine are attributed to the blockade of K + channels [delayed rectifier and K(ATP)], the stimulation of Na + -Ca( 2+ ) exchangers [2,7] , and the activation of cardiac M2 muscarinic cholinergic receptors [8] . ...
Patients with chronic aortic dissections are at high risk of catheter-induced complications. We report a Berberine is used in traditional Chinese medicine for the treatment of congestive heart failure, hypertension, diabetes, and dyslipidaemia and has a good safety profile. We report a case of a 53-year-old sportsman referred to our hospital for the onset of fatigue and dyspnoea upon exertion after he started berberine to treat hypercholesterolaemia. An electrocardiogram showed sinus bradycardia (45 bpm), first-degree atrioventricular block, and competitive junctional rhythm. An ergometric stress test showed slightly reduced chronotropic competence and the presence of runs of competitive junctional rhythm, atrial tachycardia, and sinus pauses in the recovery. After 10 d of wash-out from berberine, the patient experienced a complete resolution of symptoms, and an ergometric stress test showed good chronotropic competence. An electrocardiogram Holter showed a latent hypervagotonic state. This is the first case report that shows that berberine could present certain side effects in hypervagotonic people, even in the absence of a situation that could cause drug accumulation. Therefore, berberine's use should be carefully weighed in hypervagotonic people due to the drug's bradycardic and antiarrhythmic properties, which could became proarrhythmic, exposing patients to potential health risks.
... Both ALL and BTHP have a basic isoquinoline constitution ( Figure 1) and belong to isoquinoline alkaloid categorization. Other reports showed that several isoquinoline alkaloid agents also had antiarrhythmic effects as a series of quaternary ammonium type of antiarrhythmic drugs [40][41][42][43][44][45][46][47] . Therefore, we can speculate that ALL and BTHP, as potential antiarrhythmic agents, may be brought into use in the near future. ...
Aim:
Allocryptopine (ALL) is an alkaloid extracted from Corydalis decumbens (Thunb) Pers. Papaveraceae, whereas benzyltetrahydropalmatine (BTHP) is a derivative of tetrahydropalmatine extracted from Corydalis ambigua (Pall) Cham et Schlecht. The aim of this study was to investigate the effects of ALL and BTHP on the human ether-a-go-go related gene (hERG) current expressed in HEK293 cells.
Methods:
Cultured HEK293 cells were transiently transfected with hERG channel cDNA plasmid pcDNA3.1 using Lipofectamine. The whole-cell current IHERG was evoked and recorded using Axon MultiClamp 700B amplifier. The drugs were applied via supserfusion.
Results:
Both ALL and BTHP reversibly suppressed the amplitude and density of IHERG in concentration- and voltage-dependent manners (the respective IC50 value was 49.65 and 22.38 μmol/L). BTHP (30 μmol/L) caused a significant negative shift of the steady-state inactivation curve of IHERG, while ALL (30 μmol/L) did not affect the steady-state inactivation of IHERG. Furthermore, BTHP, but not ALL, shortened the time constants of fast inactivation and slow time constants of deactivation of IHERG. But both the drugs markedly lengthened the time constants for recovery of IHERG from inactivation. Using action potential waveform pulses, it was found that both the drugs at 30 μmol/L significantly suppressed the current densities in the late phase of action potential, but did not significantly affect the current densities in the early phase of action potential.
Conclusion:
Both ALL and BTHP derived from Chinese herbs potently block hERG current.
... Berberine, the principle compound found in Rhizoma Coptidis, has been shown to have many functions, including antimicrobial, antiarrhythmia, immunomodulatory, anti-carcinoma, antihyperlipidemic and mitigating neural disorder's functions (Iwasa et al., 1996;Li et al., 2001;Kong et al., 2004;Saha et al., 2011;Katiyar et al., 2009;Kulkarni and Dhir, 2010). Qing Kai Ling, which is an injected medication prepared by using modern pharmaceutical industrial methods, is now used to treat ischemic stroke in China in clinical settings. ...
Berberine acted as a natural medicine with multiple pharmacological activities. In the present study, we examined the effect of berberine against cerebral ischemia damage from cell cycle arrest and cell survival. Oxygen-glucose deprivation of PC12 cells and primary neurons, and carotid artery ligation in mice were used as in vitro and in vivo cerebral ischemia models. We found that the effect of berberine on cell cycle arrest during ischemia was mediated by decreased p53 and cyclin D1, increased phosphorylation of Bad (higher expression of p-Bad and higher ratio of p-Bad to Bad) and decreased cleavage of caspase 3. Meanwhile, berberine activated the PI3K/Akt pathway during the reperfusion, especially the phosphor-activation of Akt, to promote the cell survival. The neural protective effect of berberine was remained in the presence of inhibitor of mitogen-activated protein/extracellular signal-regulated kinase (MEK), but was suppressed by the inhibitors of PI3K and Akt. We demonstrated that berberine induced cell cycle arrest and cell survival to resist cerebral ischemia injury.
... However, hERG has been regarded as an important target for the pharmacological treatment of cardiac arrhythmias by class III antiarrhythmics [5]. Recent investigations indicate that berberine and resveratrol have anti-arrhythmic effects for their inhibitory actions on hERG channels [6,7]. Thus, interference with hERG channels seems to be the main mechanism explaining both the therapeutic actions and the potential cardiotoxicity of the structurally diverse compounds. ...
Liensinine and neferine, a kind of isoquinoline alkaloid, can antagonize the ventricular arrhythmias. The human ether-a-go-go-related gene (hERG) is involved in repolarization of cardiac action potential. We investigated the effects of liensinine and neferine on the biophysical properties of hERG channel and the underlying structure-activity relationships. The effects of liensinine and neferine were examined on the hERG channels in the stable transfected HEK293 cells using a whole-cell patch clamp technique, western blot analysis and immunofluorescence experiment. The pharmacokinetics and tissue distribution determination of liensinine and neferine in rats were determined by a validated RP-HPLC method. Liensinine and neferine induced decrease of current amplitude in dose-dependent. Liensinine reduced hERG tail current from 70.3±6.3 pA/pF in control group to 56.7±2.8 pA/pF in the 1 μM group, 53.0±2.3 pA/pF (3 μM) and 17.8±0.7 pA/pF (30 μM); the corresponding current densities of neferine-treated cells were 41.9±3.1 pA/pF, 32.3±3.1 pA/pF and 16.2±0.6 pA/pF, respectively. Neferine had binding affinity for the open and inactivated state of hERG channel, liensinine only bound to the open state. The inhibitory effects of liensinine and neferine on hERG current were attenuated in the F656V or Y652A mutant channels. Neferine distributed more quickly than liensinine in rats, which was found to be in higher concentration than liensinine. Both liensinine and neferine had no effect on the generation and expression of hERG channels. In conclusion, neferine is a more potent blocker of hERG channels than liensinine at low concentration (<10 μM), which may be due to higher hydrophobic nature of neferine compared with liensinine. Neferine may be safety even for long-term treatment as an antiarrhythmic drug.
... Heat-polished patch pipettes had final resistances of 2–4 MΩ when filled with a pipette solution containing (in mM): KCl 130, MgCl 2 ·6H 2 O 1, HEPES 10, Mg-ATP 5, EGTA 5, and GTP 0.1 (pH 7.3 with KOH). The extracellular solution contained (in mM): 136 NaCl, 5.4 KCl, 5 HEPES, 1 MgCl 2 ⋅6H 2 O, 1 CaCl 2 and 10 glucose (pH 7.4 with NaOH; Li et al. 2001; Yang et al. 2007). The final drug concentrations were prepared daily from Nef stock solution by diluting with extracellular solution. ...
We studied the effects of isoquinoline alkaloid neferine (Nef) extracted from the seed embryo of Nelumbo nucifera Gaertn on Human ether-à-go-go-related gene (HERG) channels stably expressed in human embryonic kidney (HEK293) cells using whole-cell patch clamp technique, western blot analysis and immunofluorescence experiment. Nef induced a concentration-dependent decrease in current amplitude according to the voltage steps and tail currents of HERG with an IC50 of 7.419 μM (n
H −0.5563). Nef shifted the activation curve in a significantly negative direction and accelerated recovery from inactivation and onset of inactivation, however, slowed deactivation. In addition, it had no significant influence on steady-state inactivation curve. Western blot and immunofluorescence results suggested Nef had no significant effect on the expression of HERG protein. In summary, Nef can block HERG K+ channels that functions by changing the channel activation and inactivation kinetics. Nef has no effect on the generation and trafficking of HERG protein. A blocked-off HERG channel was one mechanism of the anti-arrhythmic effects by Nef.
Alkaloids are naturally occurring compounds with complex structures found in natural plants. To further improve the understanding of plant alkaloids, this review focuses on the classification, toxicity and mechanisms of action, providing insight into the occurrence of alkaloid-poisoning events and guiding the safe use of alkaloids in food, supplements and clinical applications. Based on their chemical structure, alkaloids can be divided into organic amines, diterpenoids, pyridines, isoquinolines, indoles, pyrrolidines, steroids, imidazoles and purines. The mechanisms of toxicity of alkaloids, including neurotoxicity, hepatoxicity, nephrotoxicity, cardiotoxicity and cytotoxicity, have also been reviewed. Some cases of alkaloid poisoning have been introduced when used as food or clinically, including accidental food poisoning, excessive consumption, and poisoning caused by the improper use of alkaloids in a clinical setting, and the importance of safety evaluation was illustrated. This review summarizes the toxicity and mechanism of action of alkaloids and provides evidence for the need for the safe use of alkaloids in food, supplements and clinical applications.
Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality, imposing an increasing global health burden. Cardiac ion channels (voltage-gated NaV, CaV, KVs, and others) synergistically shape the cardiac action potential (AP) and control the heartbeat. Dysfunction of these channels, due to genetic mutations, transcriptional or post-translational modifications, may disturb the AP and lead to arrhythmia, a major risk for CVD patients. Although there are five classes of anti-arrhythmic drugs available, they can have varying levels of efficacies and side effects on patients, possibly due to the complex pathogenesis of arrhythmias. As an alternative treatment option, Chinese herbal remedies have shown promise in regulating cardiac ion channels and providing anti-arrhythmic effects. In this review, we first discuss the role of cardiac ion channels in maintaining normal heart function and the pathogenesis of CVD, then summarize the classification of Chinese herbal compounds, and elaborate detailed mechanisms of their efficacy in regulating cardiac ion channels and in alleviating arrhythmia and CVD. We also address current limitations and opportunities for developing new anti-CVD drugs based on Chinese herbal medicines.
Cardioprotective effects of pomegranate (Punica granatum) have been discovered in recent years. This study was aimed to assess the potential antiarrhythmic activity of pomegranate juice in isolated rat hearts subjected to hypoxia and reperfusion. The antiarrhythmic effects of the juice were studied in two phases: first, the isolated hearts of anesthetized rats were subjected to 30 min global ischemia and 90 min reperfusion. In four groups (n = 9 each), hearts received the pomegranate juice via Krebs solution at 0 (control), 1, 2 or 4% concentration. For the second phase, two groups of rats (n = 10) were gavaged with placebo (control) or pomegranate juice (4 mL kg-1 BW d-1) for three weeks. The isolated hearts from these animals underwent 30 min ischemia and 90 min reperfusion. The occurrence of single and salvo arrhythmias, ventricular tachycardia, and ventricular fibrillation were significantly lower in the juice-treated test groups in both phases of the study. Thus, results suggest strong protective effects of pomegranate juice against ischemia and reperfusion-induced arrhythmias in isolated rat hearts.
Sickle cell anemia (SCA) is an inherited disorder in the β-globin chain of hemoglobin that affects millions of people around the world, especially children. This disease prevalently occurs in some Mediterranean and Saharan Africa. For the treatment of SCA patients, a wide range of drugs have been explored by targeting antisickling activity, γ-globulin induction, antiplatelet effect, etc., but hardly a few drugs have shown potential to combat with this complex disease phenomenon. In spite of unprecedented advances in modern system of medicine, people in the disease-prone area have been taking traditional medicinal plants or plant-derived products to increase the life span of patients. Moreover, numerous clinical trials have been going on for the use of natural products under the purview of symptomatic management of SCA. This chapter is focused on the effect of natural products in pure form or characterized phytoconstituents on particularly inhibition of hemoglobin polymerization. This summarized information will be beneficial for further exploration of new therapeutics in the treatment arena of SCA.
Berberine, an isoquinoline alkaloid isolated from the Chinese herb Coptis chinensis and other Berberis plants, has a wide range of pharmacological properties. Berberine can be used to treat many diseases, such as cancer and digestive, metabolic, cardiovascular, and neurological diseases. Berberine has protective capacities in digestive diseases. It can inhibit toxins and bacteria, including Helicobacter pylori, protect the intestinal epithelial barrier from injury, and ameliorate liver injury. Berberine also inhibits the proliferation of various types of cancer cells and impedes invasion and metastasis. Recent evidence has confirmed that berberine improves the efficacy and safety of chemoradiotherapies. In addition, berberine regulates glycometabolism and lipid metabolism, improves energy expenditure, reduces body weight, and alleviates nonalcoholic fatty liver disease. Berberine also improves cardiovascular hemodynamics, suppresses ischemic arrhythmias, attenuates the development of atherosclerosis, and reduces hypertension. Berberine shows potent neuroprotective effects, including antioxidative, antiapoptotic, and anti-ischemic. Furthermore, berberine exerts protective effects against other diseases. The mechanisms of its functions have been extensively explored, but much remains to be clarified. This article summarizes the main pharmacological actions of berberine and its mechanisms in cancer and digestive, metabolic, cardiovascular, and neurological diseases.
Covering: 1996–December 2016
The human Ether-à-go-go Related Gene (hERG) channel is a voltage-gated potassium channel playing an essential role in the normal electrical activity in the heart. It is involved in the repolarization and termination of action potentials in excitable cardiac cells. Mutations in the hERG gene and hERG channel blockage by small molecules are associated with increased risk of fatal arrhythmias. Several drugs have been withdrawn from the market due to hERG channel-related cardiotoxicity. Moreover, as a result of its notorious ligand promiscuity, this ion channel has emerged as an important antitarget in early drug discovery and development. Surprisingly, the hERG channel blocking profile of natural compounds present in frequently consumed botanicals (i.e. dietary supplements, spices, and herbal medicinal products) is not routinely assessed. This comprehensive review will address these issues and provide a critical compilation of hERG channel data for isolated natural products and extracts over the past two decades (1996–2016). In addition, the review will provide (i) a solid basis for the molecular understanding of the physiological functions of the hERG channel, (ii) the translational potential of in vitro/in vivo results to cardiotoxicity in humans, (iii) approaches for the identification of hERG channel blockers from natural sources, (iv) future perspectives for cardiac safety guidelines and their applications within phytopharmaceuticals and dietary supplements, and (v) novel applications of hERG channel modulation (e.g. as a drug target).
We explored the possible link between the expression of HERG gene and cardiomyopathy in children. From April 2013 to April 2015,73 children with cardiac arrhythmia who were treated were enrolled in the present study to serve as the observation group. At the same time,76 normal individuals were also enrolled as the control group. HERG expression level in the observation group was compared with the control group. To determine the level of HERG gene expression we used fluorescent directional PCR,enzyme immunoassay and western blot analysis. The results showed that HERG mRNA level in the observation group was significantly higher than that of the control group. The level of HERG protein in the observation group was significantly higher as well. In the observation group,HERG expression gradually increased with time during the course of the disease. This result suggested that HERG gene expression was associated with the severity of cardiac arrhythmia in children. HERG expression may be the cause of deterioration in cardiomyopathy. The results have provided a theoretical and practical basis for the diagnosis and treatment of children cardiomyopathy. Thus,we established a correlation between HERG expression and cardiac arrhythmia in children.
Berberine (BBR) is a natural alkaloid isolated from the Coptis chinensis. While this plant has been used in Chinese medicine for more than 2500 years, interest in its effects in treating cardiovascular disease has been growing in the last decade. Recent researches showed that BBR had the effect of anti-heart failure, anti-hypertension, anti-hyperlipidemia, anti-insulin resistance, anti-arrhythmias, and anti-platelet aggregation.
Secondary metabolites of berberine, palmatine and jatrorrhizine are important medicinal alkaloids from amur cork tree(Phellodendron amurense), we sampled 65 natural trees of different ages in 5 forestry bureaus of Jilin Province, northeastern China. The variations of three alkaloid contents in organs were analyzed among different seasons with RP-HPLC. The results were shown as follows: the berberine contents of root, perennial branch, annual branch and leaf existed significant variance with the season changing, and the content values of root, perennial branch and annual branch reached minimum in summer basically, the berberine content of leaf increased from spring to autumn at all 3 age phases, and the variance ranged between 0.017 and 0.124 mg/g, the berberine content sequence of organs was root (24.27 mg/g in average), trunk, perennial branch, annual branch and leaf; the palmatine content of root, trunk, annual branch, leaf and the perennial branch in juvenile phase got the significant seasonal variance, the content of root, trunk, annual branch and the perennial branch in juvenile phase reached the maximum value in autumn coincidently, the palmatine content of leaves got the maximum value in all 3 age phases in spring, and the organ content sequence of palmatine was trunk (7.02 mg/g in average), perennial branch, root, annual branch; the jatrorrhizine content of trunk, perennial branch, annual branch, leaf and root in mature age phase had the significant seasonal variance, the content of most organs (except leaf) got the maximum value in summer, the jatrorrhizine content of leaf reached the maximum in spring in all 3 age phases, and the organ content sequence of jatrorrhizine was root (0.84 mg/g), trunk, perennial branch, annual branch and leaf.
As is well-known, hERG plays an essential role in phase III repolarization of cardiac action potentials. Blocking of hERG channels can lead to LQTS. Inhibition of the metabolism of CYPs activities may elevate plasma levels, to further increase accumulation of drug on cardiac. The elevated serum levels may however elicit unexpected toxicities. Therefore, the inhibition tests of hERG and CYP are central to the preclinical studies because they may lead to severe cardiac toxicity. Berberine is widely used as an antibacterial agent and often combined with macrolides to treat gastropathy. Our objective was to assess cardiac toxicity during the combined use of Berberine with macrolides. (1) Azithromycin reduced hERG currents by accelerated channel inactivation. (2) The combination of Berberine with Azithromycin reduced hERG currents, producing an inhibitive effect stronger than use of a single drug alone, due to the high binding affinity for the onset of inactivation. (3) When cells were perfused concomitantly with Berberine and Clarithromycin, they showed a stronger inhibitive effect on hERG currents by decreasing the time constant for the onset of inactivation. (4) The combined administration of Berberine with Clarithromycin had a powerful inhibitive effect on CYP3A activities than use of a single drug alone. Collectively, these results demonstrated that concomitant use of Berberine with macrolides may require close monitoring because of potential drug toxicities, especially cardiac toxicity.
Copyright © 2015. Published by Elsevier B.V.
Berberine (BBR) is an organic small molecule isolated from various plants that have been used in traditional Chinese medicine. Isolation of this compound was its induction into modern medicine, and its usefulness became quickly apparent as seen in its ability to combat bacterial diarrhea, type 2 diabetes, hypercholesterolemia, inflammation, heart diseases, and more. However, BBR's effects on neurodegenerative diseases remained relatively unexplored until its ability to stunt Alzheimer's disease (AD) progression was characterized. In this review, we will delve into the multi-faceted defensive capabilities and bio-molecular pathways of BBR against AD, Parkinson's disease (PD), and trauma-induced neurodegeneration. The multiple effects of BBR, some of which enhance neuro-protective factors/pathways and others counteract targets that induce neurodegeneration, suggest that there are many more branches to the diverse capabilities of BBR that have yet to be uncovered. The promising results seen provide a convincing and substantial basis to support further scientific exploration and development of the therapeutic potential of BBR against neurodegenerative diseases.
Chelidonium majus or greater celandine is spread throughout the world, and it is a very common and frequent component of modern phytotherapy. Although C. majus contains alkaloids with remarkable physiological effect, moreover, safety pharmacology properties of this plant are not widely clarified, medications prepared from this plant are often used internally. In our study the inhibitory effect of C. majus herb extracts and alkaloids on hERG potassium current as well as on cardiac action potential were investigated. Our data show that hydroalcoholic extracts of greater celandine and its alkaloids, especially berberine, chelidonine and sanguinarine have significant hERG potassium channel blocking effect. These extracts and alkaloids also prolong the cardiac action potential in dog ventricular muscle. Therefore these compounds may consequently delay cardiac repolarization, which may result in the prolongation of the QT interval and increase the risk of potentially fatal ventricular arrhythmias.
Copyright © 2014. Published by Elsevier B.V.
The interaction between bovine hemoglobin (BHb) and palmatine hydrochloride (PMT) was investigated at different temperatures using multispectroscopy, as well as the effect of common metal ions (Ca(2+) , Mg(2+) , Zn(2+) , Cu(2+) , Fe(2+) , Fe(3+) , Co(2+) , Ni(2+) ) on the BHb-PMT system. Results showed that the quenching mechanism of PMT on BHb was a static process. The electrostatic force played an important role in the conjugation reaction between BHb and PMT. The order of magnitude of the binding constants (Ka ) was 10(4) , and the number of binding sites (n) in the binary system was ~ 1. The binding distance (r) was ~ 2.44 nm and the primary binding for PMT was located at β-37 tryptophan in the hydrophobic cavity of BHb. In addition, the Hill's coefficients were ~ 1. Synchronous and circular dichroism spectra revealed that the microenvironment and the conformation of BHb were changed during the binding reaction. Copyright © 2013 John Wiley & Sons, Ltd.
Objective:
Insulin resistance plays an important role in the pathogenesis of diabetic cardiomyopathy. Berberine (BBR) is a plant alkaloid which promotes hypoglycemia via increasing insulin sensitivity in peripheral tissues. Little is known of BBR's role in regulating glucose metabolism in heart.
Materials/methods:
We examined the effect and mechanism of BBR on glucose consumption and glucose uptake in insulin sensitive or insulin resistant rat H9c2 cardiomyocyte cells. H9c2 myoblast cells were differentiated into cardiomyocytes and incubated with insulin for 24h to induce insulin resistance.
Results:
BBR-treatment of H9c2 cells increased glucose consumption and glucose uptake compared to controls. In addition, BBR-treatment attenuated the reduction in glucose consumption and glucose uptake in insulin resistant H9c2 cells. Compound C, an inhibitor of AMP-activated protein kinase (AMPK), abolished the enhancement of glucose consumption and glucose uptake mediated by BBR in both insulin sensitive and insulin resistant H9c2 cells compared to controls.
Conclusion:
BBR significantly increased AMPK activity, but had little effect on the activity of protein kinase B (AKT) in insulin resistant H9c2 cells, suggesting that berberine improves insulin resistance in H9c2 cardiomyocytes at least in part via stimulation of AMPK activity.
The present study was designed to elucidate the potential mechanism underlying that berberine suppressed ischemic arrhythmias in a rat model of diabetes mellitus (DM). Streptozotocin (STZ)-induced diabetic rats were subjected to ischemia by the occlusion of left anterior descending (LAD) coronary artery. Berberine was orally administered for 7 days before ischemic injury in diabetic rats. Whole-cell patch-clamp was performed to measure the transient outward K⁺ current (I(to)) and L-type Ca²⁺ current (I(Ca)). Results showed that oral administration of berberine (100 mg/kg) attenuated ischemia-induced arrhythmias in diabetic rats. Berberine significantly shortened the prolonged QTc interval from 214 ± 6ms to 189 ± 5ms in ischemic diabetic rats, and also restored the diminished I(to) and I(Ca) current densities in the same animal model rats. In conclusion, the ability of berberine to protect diabetic rats against cardiac arrhythmias makes it possible to be a prospective therapeutic agent in clinical management of cardiac disease secondary to diabetes.
The fluorescence spectra of berberine, palmatine, jatrorrhizine, and coptisine in ionic liquids were studied and found to increase significantly in ionic liquids, with [C(8)MIM][PF(6)] having the greatest increase. Further studies showed that these drugs could be extracted from an aqueous solution by [C(8)MIM][PF(6)] using the temperature-assisted ionic liquid dispersive liquid phase microextraction method. The enrichment factors were 81.8-82.3, and the extraction recovery was 98.5%, 98.1%, 98.3%, and 98.8% for berberine, palmatine, jatrorrhizine, and coptisine, respectively. Based on the [C(8)MIM][PF(6)] preconcentration, separation, and sensitized fluorescence for these drugs, a new selective and sensitive method for the determination of concentration of these four drugs in aqueous samples was presented. At optimum conditions, the linear relationship was obtained in the ranges of 0.8-130 ng mL(-1), 0.9-160 ng mL(-1), 0.7-140 ng mL(-1), and 0.6-110 ng mL(-1), respectively. The proposed method was successfully applied for the determination of the drugs in pharmaceutical preparations, urine, and plasma samples.
Cyclovirobuxine D (CVB-D) has been widely used for treatment of cardiac insufficiency and arrhythmias in China. The antiarrhythmic and proarrhythmic potential of this drug might be concerned with prolongation of action potential duration and QT interval. Human-ether-a-go-go-related gene (HERG) has an important role in the repolarization of the cardiac action potential. This study investigated for the first time the effect of CVB-D on HERG channels stably expressed in HEK293 cells using the whole-cell patch-clamp technique. CVB-D inhibited HERG current (IHERG) in a concentration-dependent manner with an IC50 of 19.7 μM. IHERG blockade required channel activation and was time-dependent, suggesting an open channel block. Moreover, IHERG inhibition by CVB-D was relieved by depolarization to a highly positive membrane potential (+80 mV) that favored HERG channel inactivation. These findings suggested that CVB-D inhibit HERG channels in the open states. CVB-D had no effect on HERG current kinetics. Thus, we conclude that CVB-D inhibits HERG encoded potassium channels and this action might be a molecular mechanism for the previously reported APD prolongation and QT interval prolongation with this drug.
Berberine, an herbal alkaloid, has been reported to have promotion potential of apoptosis and anticancer effect on a variety of human tumor cells. To obtain more specific understanding of those consequences of berberine on hepatocellular carcinoma (HCC) and the tumor microenvironment, we conducted in vitro experiments to investigate the inhibitory effect of berberine on tumor-induced angiogenesis using HCC cells and human umbilical vein endothelial cells (HUVECs).
Human umbilical vein endothelial cell growth was quantified with the CCK-8 cell proliferation assay; cell migration was observed with a Boyden chamber (Transwell, Corning, Lowell, MA, USA), and angiogenesis was assessed by endothelial tube formation in Matrigel in vitro. In addition, VEGF level was determined by ELISA and VEGF mRNA expression by RT-PCR.
Berberine inhibited the capacity of HCC to stimulate HUVEC's proliferation, migration and endothelial tube formation, suggesting that berberine could influence the cross-talk between the HCC cell and vascular endothelial cells. These results demonstrate berberine's antiangiogenesis property and its clinical potential as an inhibitor of tumor angiogenesis. Subsequently analyses reveal that berberine prevents secretion of VEGF from HCC and down-regulates VEGF mRNA expression.
These findings strongly suggest that berberine is a potential antiangiogenic agent and a promising antitumor drug for HCC.
Berberine, a natural product alkaloid, has been shown to display a wide array of pharmacological effects. Generally, the mechanism of action of each of these effects has not been well described. The aim of the present study is to test the hypothesis that some of berberine's cardiovascular effects are mediated through activation of cardiac M2 muscarinic cholinergic receptors. In our studies, we tested the ability of berberine to alter the contraction rate of cultured neonatal rodent cardiomyocytes. In these spontaneously contracting primary cultured cells, berberine reduced the contraction rate in a manner independent of β-adrenergic receptor blockade but sensitive to pertussis toxin, a Gi/o G protein inhibitor. Muscarinic antagonists completely blocked the effect of berberine on contraction rate of cardiomyocytes, whereas the effect of berberine was not opposed by antagonists to opioid, adenosine or α-adrenergic receptors. Further, berberine bound to muscarinic receptors of adult mouse heart membranes with relatively high affinity (K(i)=5.4×10(-6)M) comparable to that of the classic muscarinic agonist, carbachol, and to muscarinic M2 receptors exogenously expressed in HEK 293 cells (K(i)=4.9×10(-6)M). Therefore, the findings of the present study suggest that berberine is a muscarinic agonist at M2 receptors, potentially explaining some of its reported cardiovascular effects.
Berberine is a plant alkaloid with numerous biological activities. A large body of preclinical in vitro and in vivo studies support different pharmacological actions of berberine that could be potentially useful in the management of metabolic diseases associated with high cardiovascular disease risk, such as mixed hyperlipidemia, insulin resistance, metabolic syndrome, and type 2 diabetes. Moreover, it seems that berberine also exerts anti-inflammatory and antiproliferative effects that could play a role in the development of atherosclerosis and its clinical consequences. Recently, the metabolic effects of berberine have been demonstrated in humans, opening new perspectives for the use of this molecule in patient therapy. Larger and longer clinical studies need to be carried out to implement the definition of the therapeutic role of berberine in humans.
It was recently suggested that the antiarrhythmic effect of propranolol, a ss-adrenoceptor antagonist, on ischemic myocardium includes restoration of I(K1) current and Cx43 conductance; however, little is known whether effects on the transient outward current I(to) contribute. A model of myocardial infarction (MI) by ligating the left anterior descending coronary artery was established. Propranolol was given 1 h or daily for 3 months, whole-cell patch-clamp techniques were used to measure I(to). Kv4.2 and PKA levels were analyzed by Western blot and cAMP level was determined by radioimmunoassay. The results showed that propranolol decreased the incidence of arrhythmias induced by acute ischemia and mortality in 3 month MI rats. Propranolol restored the diminished I(to) density and Kv4.2 protein in MI hearts. In addition, neonatal cardiomyocyte pretreatment with propranolol or administrated after hypoxia can resume I(to) density. cAMP/PKA was enhanced in acute MI, the reason of decreased Kv4.2 expression. Treatment with propranolol prevented the increased cAMP/PKA in 1 h MI, whereas propranolol had little effect on decreased cAMP/PKA in 3 months MI. This study demonstrated that both short- and long-term propranolol administrations protect cardiomyocytes against arrhythmias and mortality caused by cardiac ischemia; the involvement of cAMP/PKA signal pathway in the regulation of propranolol on I(to) acted differently along with the ischemic progression.
In contrast to other members of the Eag family of voltage-gated, outwardly rectifying potassium channels, the human eag-related
gene (HERG) has now been shown to encode an inwardly rectifying potassium channel. The properties of HERG channels are consistent
with the gating properties of Eag-related and other outwardly rectifying, S4-containing potassium channels, but with the addition
of an inactivation mechanism that attenuates potassium efflux during depolarization. Because mutations in HERG cause a form
of long-QT syndrome, these properties of HERG channel function may be critical to the maintenance of normal cardiac rhythmicity.
Long QT syndrome (LQT) is an autosomal dominant disorder that can cause sudden death from cardiac arrhythmias. We recently discovered that mutations in HERG, a K+-channel gene, cause chromosome 7-linked LQT. Heterologous expression of HERG in Xenopus oocytes revealed that HERG current was similar to a well-characterized cardiac delayed rectifier K+ current, IKr, and led to the hypothesis that mutations in HERG reduced IKr, causing prolonged myocellular action potentials. To define the mechanism of LQT, we injected oocytes with mutant HERG complementary RNAs, either singly or in combination with wild-type complementary RNA. Some mutations caused loss of function, whereas others caused dominant negative suppression of HERG function. These mutations are predicted to cause a spectrum of diminished IKr and delayed ventricular repolarization, consistent with the prolonged QT interval observed in individuals with LQT.
The effects of berberine, an isoquinoline alkaloid, were investigated in human myeloma cells. In cells with intracellular Ca2+ concentration ([Ca2+]i) = 10 nM, the depolarizing square pulses from -80 mV elicited an instantaneous outward current with an inactivation. This outward current was voltage dependent, activating at -30 mV and showed inactivation with repetitive depolarization, and was hence believed to be n type voltage-activated K+ current (IK(V)). Berberine (30 microM) produced a prolongation in the recovery of IK(V) inactivation. In cells with [Ca2+]i = 1 microM, berberine also inhibited A23187-induced IK(Ca). Berberine (1-300 microM) caused the inhibition of IK(V) and IK(Ca) in the concentration-dependent manners. The IC50 values of berberine-induced inhibition of IK(V) and IK(Ca) were approximately 15 microM and 50 microM, respectively. In inside-out configurations, berberine inside the pipette suppressed the activity of K(Ca) channels without changing the single channel conductance. Berberine also inhibited the proliferation of this cell line and the IC50 value of berberine-induced inhibition of cell proliferation was 5 microM. Thus, the cytotoxic effect of berberine in cancer cells may be partially explained by its direct blockade of these K+ channels.
The effect of artemisinin (Art) on one of major types of cloned inward rectifier potassium channel (K(ir2.1) channel) expressed in Xenopus oocytes was examined using a two electrode voltage clamp. Art reduced the functional expression of K(ir2.1) channels in Xenopus oocytes in a concentraction-dependent manner when the oocytes were perfused by Art after cRNA injection. Art blocked the K(ir2.1) channels also in voltage-dependent fashion. When command voltage was -140, -130 and -120 mV, Art in 5 and 50 μmol · L-1 reduced the inward current through K(ir2.1) channel by 14.2%, 34.5%; 12.0%, 24.6%; 4.3%, 19.1%, respectively. When command voltage was -50, -40 and -30 mV, Art in 5 and 50 μmol · L-1 increased the outward current through K(ir2.1) channel by 22.2%, 72.2%; 28.0%, 80.0%; 24.1%, 69.0%, respectively. The blockade of Art on the K(ir2.1) channels was recovered after washing using normal perfusing solution. The results suggest that the antiarrhythmic action of Art is caused by its blocking effect on K(ir2.1) channels.
The effects of berberine on slow-response action potentials (SAP) of guinea pig papillary muscles were studied. SAP was elicited by histamine in a high concentration of potassium solution (27 mmol). The results showed that berberine (24.5 mumol) was able to increase action potential amplitude, maximum rate of depolarization, action potential duration 50, action potential duration 100 (n = 16, p less than 0.01) and effective refractory period (n = 10, p less than 0.01) of SAP by 6.2%, 21.1%, 50.1%, 47.2% and 92.2%, respectively, but did not affect the resting membrane potential (RMP). To the above parameters, except APD 100, berberine was no longer to induce any significant change by pretreating with propranolol. The results suggested that the effects of berberine on slow-response action potentials were mainly related to the facilitating of slow calcium inward current, which might result from stimulating the beta-adrenoceptor.
Antiarrhythmic agents can worsen existing arrhythmias by increasing their duration or frequency, increasing the number of premature complexes or couplets, altering the rate of the arrhythmia or causing new, previously unexperienced arrhythmias. QT prolongation occurs in many settings, not all of which are associated with increased arrhythmia development. Arrhythmogenesis in the setting of a long QT interval may be related to marked asynchrony of repolarization. The role of afterdepolarizations is still being investigated. No correlation has been established between the occurrence of torsades de pointes, a specific degree of QT prolongation and either the dose or serum concentration of any of the antiarrhythmic agents. In 30 patients who experienced drug-induced ventricular fibrillation, the median time to ventricular fibrillation was only 3 days after drug treatment began. Significant caution must be exercised in determining the need for antiarrhythmic therapy and in monitoring patients after treatment has begun.
Mutations in HERG cause an inherited cardiac arrhythmia, long QT syndrome (LQT). To define the function of HERG, we expressed the protein in Xenopus oocytes. The biophysical properties of expressed HERG are nearly identical to the rapidly activating delayed rectifier K+ current (IKr) in cardiac myocytes. HERG current is K+ selective, declines with depolarizations above 0 mV, is activated by extracellular K+, and is blocked by lanthanum. Interestingly, HERG current is not blocked by drugs that specifically block IKr in cardiac myocytes. These data indicate that HERG proteins form IKr channels, but that an additional subunit may be required for drug sensitivity. Since block of IKr is a known mechanism for drug-induced cardiac arrhythmias, the finding that HERG encodes IKr channels provides a mechanistic link between certain forms of inherited and acquired LQT.
The effects of berberine on potassium channel subtypes were investigated by using patch-clamp whole cell recording techniques. Berberine is known to be effective in lowering blood glucose and ameliorating arrhythmia. Our results indicate that, berberine can prolong action potential duration (APD), decrease IK1 and outward Itail, but showed no effect on IK. In addition, berberine was also shown to antagonize cromakalim (BRL-34915) induced inhibition of APD and the increase of KATP. These suggest that berberine can inhibit voltage- dependent and ATP-sensitive potassium channels. It appears that the mechanisms of antiarrhythmic and antidiabetic action of berberine might be due to its potassium channel blocking effects.
Conventional microelectrode techniques were used for intracellular recordings of the transmembrane electrical potentials, the effects of berberine were studied on canine cardiac Purkinje and ventricular muscle fibres and on rabbit atrial fibres.
Berberine (3–30 μ m ) increased in a concentration‐dependent manner, the action potential duration (APD) in canine Purkinje and ventricular muscle without affecting other parameters of the action potential.
The berberine‐induced enlargement of the APD showed reverse use‐dependence, so that the effect was greater at lower rates of stimulation.
Preparations perfused with berberine (30 μ m ) and driven at rates below 0.5 Hz exhibited early after depolarizations which persisted 3–4 h after washing.
The early afterdepolarizations were reversibly abolished by perfusion with lignocaine (3 μ m ) or by the increase in the rate of stimulation.
The effective refractory period (ERP) of Purkinje fibres was greatly increased by berberine (30 μ m ); however, the ratio ERP/APD was not significantly affected.
Berberine (10–100 μ m ) decreased in a concentration‐dependent manner the spontaneous frequency of rabbit sinoatrial cells. The decrease in frequency was accompanied by a depression of the phase 4 depolarization, without significant changes in other parameters of the nodal action potential.
Atropine (2.5 μ m ) did not affect the bradycardic effect of berberine. On the other hand, berberine (30 μ m ) did not alter the chronotropic effect of isoprenaline.
Berberine (30 μ m ) also increased the duration of slow responses in K‐depolarized rabbit atrial muscle fibres, other parameters being unaffected.
It is suggested that berberine exerts Class III antiarrhythimic and proarrhythmic actions in cardiac muscle of the dog in vitro .
The effects of berberine on ion transport in both human colonic mucosal epithelia and an intestinal epithelial cell line (T84) were examined. Berberine (concentration range 0-500 microM) reduced both basal and stimulated ion transport responses in human colonic mucosae in a manner which was non-specific for Ca2+ -or cAMP-mediated signals. Similarly, in cultured intestinal epithelial monolayers, berberine inhibited Ca2+ -and cAMP-mediated responses indicating an inhibitory activity directly at the level of the epithelium rather than an indirect effect through other mucosal element(s). Berberine did not alter the rate of generation of cAMP by adenylyl cyclase or the activity of protein kinase A, the effector enzyme of the cAMP pathway. Berberine inhibited carbachol-stimulated 86Rb+ efflux from T84 monolayers. Berberine also inhibited K+ conductance in apically-permeabilised re-sected mucosae. These results indicate i) that berberine exerts an anti-secretory action directly upon epithelial cells and ii) the mechanism of action may be at the level of blockade of K+ channels.