Research Progress on Natural Products’ Therapeutic Effects on Atrial Fibrillation by Regulating Ion Channels

Abstract

Antiarrhythmic drugs (AADs) have a therapeutic effect on atrial fibrillation (AF) by regulating the function of ion channels. However, several adverse effects and high recurrence rates after drug withdrawal seriously affect patients’ medication compliance and clinical prognosis. Thus, safer and more effective drugs are urgently needed. Active components extracted from natural products are potential choices for AF therapy. Natural products like Panax notoginseng (Burk.) F.H. Chen, Sophora flavescens Ait., Stephania tetrandra S. Moore., Pueraria lobata (Willd.) Ohwi var. thomsonii (Benth.) Vaniot der Maesen., and Coptis chinensis Franch. have a long history in the treatment of arrhythmia, myocardial infarction, stroke, and heart failure in China. Based on the classification of chemical structures, this article discussed the natural product components’ therapeutic effects on atrial fibrillation by regulating ion channels, connexins, and expression of related genes, in order to provide a reference for development of therapeutic drugs for atrial fibrillation.

Full text

Review Article
Research Progress on Natural Products’Therapeutic Effects on
Atrial Fibrillation by Regulating Ion Channels
Jinshan He ,
1
Sicong Li ,
2
Yumeng Ding ,
3
Yujia Tong ,
4
and Xuebin Li
1
1
Cardiovascular Department, Peking University People’s Hospital, Beijing, China
2
School of Pharmacy, Peking University Health Science Centre, Beijing, China
3
School of Life Sciences, Shanxi Normal University, Shanxi, China
4
Institute of Medical Information, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing, China
Correspondence should be addressed to Xuebin Li; docxuebin.li@vip.sina.com
Received 26 August 2021; Revised 28 January 2022; Accepted 3 March 2022; Published 22 March 2022
Academic Editor: Simona Saponara
Copyright © 2022 Jinshan He et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Antiarrhythmic drugs (AADs) have a therapeutic effect on atrial fibrillation (AF) by regulating the function of ion channels.
However, several adverse effects and high recurrence rates after drug withdrawal seriously affect patients’medication
compliance and clinical prognosis. Thus, safer and more effective drugs are urgently needed. Active components extracted
from natural products are potential choices for AF therapy. Natural products like Panax notoginseng (Burk.) F.H. Chen,
Sophora flavescens Ait., Stephania tetrandra S. Moore., Pueraria lobata (Willd.) Ohwi var. thomsonii (Benth.) Vaniot der
Maesen., and Coptis chinensis Franch. have a long history in the treatment of arrhythmia, myocardial infarction, stroke, and
heart failure in China. Based on the classification of chemical structures, this article discussed the natural product components’
therapeutic effects on atrial fibrillation by regulating ion channels, connexins, and expression of related genes, in order to
provide a reference for development of therapeutic drugs for atrial fibrillation.
1. Introduction
Atrial fibrillation (AF) is associated with a higher risk of
stroke, heart failure with reduced ejection fraction, cardiomy-
opathy, acute coronary syndrome, and impaired quality of life.
As shown in Figure 1, the pathophysiological changes of atrial
fibrillation include oxidative stress, atrial structure, electrical
remodeling, autonomic nerve dysfunction, metabolic abnor-
malities, ectopic activation, and reentry. AF treatment mainly
includes rate and rhythm control therapy, anticoagulation,
and left atrial appendage closure. Restoration and maintaining
sinus rhythm have shown superiority in improving survival,
quality of life, and ventricular function and reducing heart fail-
ure hospitalization. British National Institute for Health and
Care Excellence (NICE) guideline [1], 2019 American Heart
Association (AHA)/American College of Cardiology (ACC)/
Heart Rhythm Society (HRS) AF guideline [2], and 2020 the
European Association of Cardio-Thoracic Surgery (EACTS)
[3] all recommended catheter ablation (mainly including
radiofrequency ablation and cryoballoon ablation) for sinus
rhythm recovery in patients with atrial fibrillation. However,
after primary catheter ablation, the recurrence rate of AF/AF
is high, especially in patients with severe structural cardiac
remodeling, chronic kidney disease, and hyperthyroidism.
Some patients have to receive more than one catheter ablation
or be followed with electric cardioversion [4].
AADs have a therapeutic effect on atrial fibrillation by
regulating potassium, calcium, sodium channels, or β1
receptors. However, adverse reactions can seriously affect
the prognosis of patients with atrial fibrillation. Propafenone,
sotalol, and ibutilide may give rise to severe ventricular
arrhythmia. Amiodarone may cause interstitial lung disease,
thyroid dysfunction, and nonalcoholic fatty liver disease.
Natural products have unique advantages in antiarrhythmia,
with few side effects and rarely inducing other arrhythmias.
In recent years, it has become a hotspot to search for antiar-
rhythmia active ingredients from natural products. In this
article, natural products with effects on more than two kinds
of ion channels were included. By taking chemical structure
as classification standard, natural products’antiarrhythmic
Hindawi
Cardiovascular erapeutics
Volume 2022, Article ID 4559809, 23 pages
https://doi.org/10.1155/2022/4559809

effects on ion channels and target genes were discussed in
detail to lay a foundation for the follow-up research and
development of antiarrhythmic drugs.
2. Ion Channels and Connexins in the
Pathogenesis of Atrial Fibrillation
As signal detectors, relayers, and amplifiers, ion channels
regulate signal transduction and ion transport across cell
membranes [5]. The abnormal function of ion channels
increases vulnerablity and sustainability of AF [6]. Recur-
rence of atrial fibrillation can lead to a shorter effective
refractory period of atrial myocytes, increased dispersion,
and decreased or disappearance of frequency adaptability,
thus promoting the deterioration of paroxysmal atrial fibril-
lation into persistent atrial fibrillation. Moreover, ion chan-
nel coding genes related to atrial fibrillation have also been
discovered. In patients with atrial fibrillation, decreased
expression of L-type Ca 2 + channel, ryanodine receptor
(RyR2), potassium voltage-gated channel subfamily A
member 5 (KCNA5), sarcoplasmic reticular Ca2+-ATPase
(SERCA2), the beta-subunit MinK (KCNE1) and MIRP2
(KCNE3) [7], and increased expression of
hyperpolarization-activated cation channel two associated
with the pacemaker current I (f) (HCN2) were observed
[8]. The left atrial diameter was negatively correlated with
the expression of RyR2 and KChIP2 [7].
2.1. Potassium Channel. Four major kinds of potassium
channels have been identified in cardiovascular myocytes,
including inwardly rectifying (Kir) K+ channels, calcium-
activated potassium channel (KCa), voltage-gated (VK),
and two-pore domain potassium channels (K2P) [5]. (Kir)
current (IK1) and acetylcholine-activated potassium current
(IK, Ach) are involved in AF drivers formation (rotors and
focal impulses) [9–11]. The increase of vagus nerve tension
can enhance IKAch to shorten APD and stabilize the rotor
related to reentry [12]. KCa channels can be divided into
the big, small, and intermediate-conductance K+ channels
[13]. KCa channels are also related to atrial structural and
electrical remodeling in atrial fibrillation [14]. Transient out-
ward current (Ito), similarly to the ultrarapid current (IKur),
contributes to early repolarization [15]. By starting
membrane depolarization, VK allows K+ efflux and regu-
lates cardiac action potential duration. K2P- channels
conduct outward K+ currents and modulate action potential
repolarization [16].
2.2. Calcium Channel. L-type calcium current is the primary
inward current in the action potential plateau phase, while
T-type calcium current depolarizes current in phase 0 of
action potential duration [17]. Generated and conducted
from the sinoatrial node and atrioventricular node, L-type
Ca2+ current was not only the primary inward current in
atrial and ventricular action potential 2 phases [18]. Depo-
larization of cardiomyocytes can open the L-type calcium
channel and the influx of Ca2+ and then trigger the release
of Ca2+ from the sarcoplasmic reticulum. The process above
is essential in the excitation-contraction coupling of cardio-
myocytes [19].
Abnormal intracellular calcium (Ca2+) handling can
trigger delayed after depolarization (DADs) and thus
Atrial
brillation
Rhythm control
Rate control
Heart failure
myocardial infarction stroke
Anticoagulation
Le atrial appendage closure
(LAAC)
Electrical
remodeling
Structural
remodeling
Ectopic
focus and
reentry
Oxidative
stress
Abnormal
metabolism
Autonomic
nerve
dysfunction
ROS
Figure 1: Pathophysiological changes, treatment, and complications of atrial fibrillation.
2 Cardiovascular Therapeutics

increase atrial ectopic activity. Intracellular calcium- (Ca2
+-) calmodulin- (CaM-) calmodulin kinase (CaMK II) signal
transduction pathway plays a central role in the regulation of
intracellular calcium. Increased spontaneous sarcoplasmic
reticulum (SR) Ca2+ release leads to ryanodine receptor
(RyR2) dysregulation and Ca2+/calmodulin-dependent
protein kinase II (CaMKII) hyperactivity. Exciting βadre-
noceptors can enhance RyR2 receptor phosphorylation
and promote ectopic activation associated with delayed
depolarization [20]
2.3. Sodium Channel. The voltage-gated sodium channels
contribute to the initiation and conduction of action poten-
tial [21, 22]. Prolonging sodium influx in the plateau phase
can lead to early afterdepolarizations and ventricular tachy-
cardia [23]. The sequential activation and inactivation of
sodium channels prevent proarrhythmic events [24]. In
recent years, late sodium current has been related to atrial
fibrillation [25]. It promotes the occurrence of AF by
increasing the dispersion of repolarization and leads to
intracellular calcium overload.
2.4. Connexin. Cardiac connexins contribute to gap junc-
tions intercellular electrical and molecular signaling commu-
nication [26]. There are three different connexins in the
human heart, including Cx40, Cx43, and Cx45 [27, 28].
Connexin 45 is mainly expressed in sinus node (SA) and
atrioventricular node (AV), while connexin 43 and connexin
40 are both expressed in atrial muscle [29]. Cx40 promoter
polymorphisms that inhibit the expression of Cx40 are asso-
ciated with the early onset of AF [30]. Somatic and germline
mutations within the coding regions of the human Cx40
gene (GJA5) are also related to a higher risk of AF [31].
Atrial fibrillation leads to less connexin protein, less intercel-
lular electrical coupling, changes in the electrical conductiv-
ity of the myocardium, the conduction velocity, and an
aggravated degree of the auriculoventricular block.
2.5. Hyperpolarization-Activated Cyclic Nucleotide-Gated
Cation Channel (HCN). HCN2 and HCN4 are channels
responsible for cardiac hyperpolarization-activated cation
current (or “funny current”, If) [32, 33]. Their function
decreases in the sinoatrial node and increases in the atrial
and pulmonary vein in atrial fibrillation patients [34].
Activated by intracellular cAMP and membrane hyperpolar-
ization, cardiac hyperpolarization-activated cation current
contributes to diastolic depolarization of pacemaker cells [35].
3. Natural Products with Bioactivity in AF
3.1. Saponin. Saponins are glycosides with triterpenes or
helical steranes as aglycones. Saponins are the main practical
components of Panax notoginseng (Burkill) F. H. Chen ex C.
H., Radix Polygalae, Platycodon grandiflorus, and Radix
Bupleuri [36].
3.1.1. Panax notoginseng Saponins (PNS). Extracted from the
roots of Panax notoginseng (Burk.) F.H. Chen, PNS has
antiarrhythmia, antiplatelet [37], antishock [38], antioxida-
tion [39], sedative [40], and antitumor [41] effects. Panax
notoginseng saponins have been approved in the treatment
of central retinal vein occlusion, sequelae of cerebrovascular
disease, enophthalmos, and anterior chamber hemorrhage in
China. By regulating potassium and calcium ion channels,
PNS reduced the automaticity of cardiomyocytes, slowed
down cardiac electrical conduction, prolonged action poten-
tial duration (APD) and effective refractory period (ERP),
and prevented reentry agitation [42].
(1) Potassium Channels. PNS (150 mg/kg intraperitoneal
injected once) significantly inhibited myocardial cell apopto-
sis induced by isoproterenol in atrial fibrillation model mice
[43]. PNS significantly downregulated the expression of
miR-499 in atrial tissues compared with the control group
(P<0:05). Small conductance calcium-activated potassium
channel 3 (SK3) plays an essential role in the development
of atrial fibrillation. Knocking out the SK3 gene could trigger
atrial fibrillation. By downregulating, the expression of
potassium calcium-activated channel subfamily N member
3(KCNN3) and SK3 and microRNA-499 (miR-499) affected
the activity of the SK3 pathway and then triggered the occur-
rence of atrial fibrillation.
(2) Calcium Channel. CACNA1C gene encoded the L-type
Ca2+ channel α1 subunit (Cav1.2) [44]. PNS (0.1, 0.6, 1,
and 4 g/L) [45] inhibited L-type calcium channels (Cav1.2)
and T-type calcium channels (Cav3.1) in Xenopus laevis
oocytes in vitro. MicroRNA29 (miR29) targeted extracellular
matrix proteins. It played an important role in the atrial
fibrotic remodeling of AF and chronic heart failure patients
[46]. By regulating the expression of the ATPase sarcoplas-
mic/endoplasmic reticulum Ca2+ receptor 2(ATP2A2) gene,
miR-328 affected the intracellular Ca2+ concentration and
the expression of calcineurin [47]. CACNA1C and CACNB1
that respectively encoded α1c- and β1 subunits of cardiac L-
type Ca2+ channel were potential targets of miR-328 [48].
PNS [44] (150 mg/kg intraperitoneal injected once) signifi-
cantly upregulated the expression of miR-29b and miR-328
(P<0:05), thereby inhibiting isoproterenine-induced atrial
fibrillation. In addition, PNS reduced the release of calcium
in the sarcoplasmic reticulum, thus improving the apoptosis
of myocardial cells caused by calcium overload [49].
In addition to regulating ion channels, the therapeutic
effects of PNS on atrial fibrillation were also associated with
anti-inflammation, antifibrosis, and antioxidative stress
effects. After seven days of intraperitoneal injecting PNS
(100 μg/g), atrial fibrillation induced by ACh-CaCl2 mixed
solution was significantly inhibited with effective refractory
period prolonged, and the duration of atrial fibrillation
shortened [50]. By activating the PI3K-AKT signaling path-
way, the infiltration of inflammatory cells into cardiomyo-
cytes and blood vessels and the deposition of collagen
fibers around blood vessels were inhibited, with myocardial
fibrosis improved in rats with atrial fibrillation [51].
In clinical trials, the therapeutic effect of PNS on atrial
fibrillation has also been confirmed. Thirty-five patients with
atrial fibrillation in the treatment group were given PNS
3Cardiovascular Therapeutics

(orally taking 100 mg, tid, for six months) combined with
amiodarone (orally taking 200 mg, tid, for the first week,
200 mg bid for the second week, and continued with
200 mg once a day until six months), and 35 patients in
the control group were given amiodarone (the same dosage
as above, for six months) [52]. The AF recurrence rate in
the treatment group was significantly lower than that of
the control group (14.29% vs. 40%, P<0:05). Left atrial
diameter and ankyrin repeat expression in the treatment
group were lower than those in the control group after six
months of treatment. These results suggested that PNS
inhibited atrial remodeling and ectopic pacing.
3.2. Alkaloids. Alkaloids are alkaline organic compounds
containing nitrogen. They have alkaline properties and are
widely distributed in advanced plants, especially in dicotyle-
donous plants.
3.2.1. Berberine. Extracted from Coptis chinensis Franch. of
Ranunculaceae and Mahonia fortunei (Lindl.) Fedde of ber-
beris [53], berberine is a kind of isoquinoline alkaloid with
antiarrhythmia [54], anti-inflammatory [55], antibacterial
[56], hypoglycemia [57], vasodilation [58], and antitumor
effects [59]. In terms of antiarrhythmia, berberine can
prolong the action potential duration, and effective refrac-
tory period of myocardial cells [60] inhibits the occurrence
of atrioventricular reentrant tachycardia by regulating potas-
sium, calcium ion channels, and hyperpolarization-activated
cyclic nucleotide-gated cation channel [61].
(1) Potassium Channel. Berberine could inhibit the rapid and
slow activation of delayed rectifier outward potassium cur-
rent in cardiomyocytes [62]. Berberine (3-100 μmol/L)
inhibited cromakalim-induced outward currents in isolated
guinea-pig ventricular myocytes and ATP-sensitive K+
(KATP) channels [63]. Berberine (100 μmol/L) had a block-
ing effect on inward rectifier potassium current (IK1) and
outward delayed rectifier potassium current (IK) expressed
in Xenopus oocytes. In vivo, berberine (10 and 20 mg/kg)
inhibited the expression of KCNH2 in rat myocardium
(P<0:05) [64, 65].
(2) Calcium Channel. In vitro, berberine (10 and 30 μmol/L)
could not only inhibit the L-type and T-type calcium chan-
nel of guinea pig ventricular myocytes and inhibit extracellu-
lar Ca2+ influx but also reduce the delayed depolarizing
induced by calcium overload [66, 67]. CPU86017 was a ber-
berine derivative that could relieve heart failure by inhibiting
calcium leakage, downregulating phosphatase, and exerting
antioxidant activity [68]. Moreover, CPU86017 led to a
regression of the transmural dispersion of repolarization
and inhibition of RyR2 and SERCA2 [69].
(3) Hyperpolarization-Activated Cyclic Nucleotide-Gated
Cation Channel (HCN). Berberine (1-300 μmol/L) inhibited
the current of hyperpolarization-activated cyclic
nucleotide-gated 4 (hHCN4) channel expressed in Xenopus
laevis oocytes. Berberine decreased the rate of pacemaker
firing and diastolic depolarization and changed the potential
action parameters [70].
In clinical trials, Zheng et al. [71] conducted a retrospec-
tive cohort study of 88 patients with paroxysmal atrial fibril-
lation. Forty-five patients orally took berberine (the average
dose of 1.3 g/day for one year), and 43 patients orally took
amiodarone (0.2 g tid for the first week, 0.2 g bid for the sec-
ond one, and 0.2 g for the following weeks, lasted for one
year). There was no significant difference in the conversion
rate and echocardiographic parameters between the berber-
ine and amiodarone groups after 12 months of treatment.
Echocardiographic parameters showed that the E/A ratio
and left atrial diameter were significantly improved after 6
and 12 months of berberine treatment. However, in the ami-
odarone group, only E/A ratio got considerably enhanced.
3.2.2. Tetrandrine (Tet). Extracted from rhizomes of Tricho-
santhes Merr. Chun. of tetrandrine and roots of Stephania
discolor, Stephania tetrandra, and Aristolochia heterophylla,
tetrandrine is a kind of dibenzyl isoquinoline alkaloid [72]
with antiarrhythmia [73], antihypertensive [74], anti-
inflammatory [75], and antitumor [74] effects [76]. In terms
of antiarrhythmia, by inhibiting calcium, potassium, and
sodium channels, tetrandrine can slow down the heart rate,
inhibit atrioventricular conduction, and prolong the effective
refractory period of cardiomyocytes [77].
(1) Potassium Channel. Tetrandrine dosage-dependently
inhibited delayed rectifier potassium current. The maximum
effective concentration is 3×10
−5mol/L [18]. Tetrandrine
had a bidirectional regulation effect on calcium-activated
potassium channels. In vitro, tetrandrine (7.5 and
15 μmol/L) increased the opening frequency and prolonged
the opening time of calcium-activated potassium channels
in rabbit cardiomyocytes. However, at the concentration
of 30 μmol/L, it significantly reduced the opening
frequency and shortened the opening time of calcium-
activated potassium channels.
(2) Calcium Channel. Tetrandrine could inhibit both L-type
and T-type calcium channels in cardiomyocytes [78, 79].
Tetrandrine (6 μmol/L) could reversibly block more than
50% of the intracellular Ca2+ current in rabbits’cardiomyo-
cytes [80]. In isolated rats’cardiomyocytes, tetrandrine (100
micromol/L) reduced Ca2+ influx in the sarcolemma and
inhibited Ca2+ uptake into the sarcoplasmic reticulum by
inhibiting ATP2A2 [81]. Tet (50 mg/kg/d, intragastrically
administrated for nine weeks) [82]) significantly inhibited
calcium overload by reducing the density and the total num-
ber of dihydropyridine binding sites in the myocardium and
vessels. Tet also improved left ventricular compliance and
vascular endothelial function.
(3) Sodium Channel. Tet (10-30 μmol/L) inhibited sodium
current in single bullfrog cardiac cells [83]. Tet (40-
120 μmol/L) inhibited sodium current in cardiomyocytes
from 12 patients with atrial fibrillation without affecting
the density and properties of sodium channels [84]. The
4 Cardiovascular Therapeutics

voltage-gated cardiac sodium channel contributed to action
potential conduction [22]). Dysfunction of sodium channels
increased susceptibility to atrial fibrillation.
3.2.3. Matrine. Extracted from the dried root of Sophora
flavescent Ait. and Euchresta japonica, matrine has antiar-
rhythmia [85], antibacterial [56], antipulmonary [86],
hepatic fibrosis [87], and antitumor [88] effects. As a broad-
spectrum antiarrhythmia drug, matrine can prolong action
potential duration and effective refractory period, slow down
heart rate, improve myocardial contractility, and inhibit
ectopic rhythm and atrioventricular reentry agitation by inhi-
biting potassium, sodium, and calcium channels [89].
(1) Potassium Channel. The HERG gene (human ether-a-go-
go-related gene), also known as KCNH2, was responsible for
encoding Kv11.1 protein [90]. This potassium ion channel
activates the cardiac delayed rapid-rectifying potassium
current (IKr), which was responsible for action potential
platform and 3-phase repolarization [91, 92]. IKr, IKs, and
IK1 were repolarization reserve currents [93].
Matrine had a bidirectional regulation effect on the
HERG potassium channel [94]. In vitro, a low concentration
of marine (1 μmol/L) promoted the expression of HERG in
rats’cardiomyocytes. In contrast, a high concentration of
matrine (100 μmol/L) inhibited the expression of HERG,
prolonged the action potential duration and effective refrac-
tory period (ERP) of ventricular myocytes, gradually slowed
down the frequency of spontaneous discharge, and reduced
the incidence of ectopic rhythm [95].
M3 receptor-mediated K+ current (IKM3) has been
found to be a new target for the treatment of atrial fibrillation
in recent years. Pretreatment of matrine (15, 30, and 45 mg/
kg intravenously administrated once a day for 15 days) sig-
nificantly reduced AF incidence rate and duration time in a
dose-dependent manner. Matrine inhibited atrial repolariza-
tion by inhibiting IKM3 current, prolonged the effective
refractory period, and made the effective refractory period
in different parts of the myocardium tend to be the same,
thus blocking the atrioventricular reentry excitation [96].
Expression of the M3 receptor was decreased, and Cav1.2
expression was upregulated on the atrial membrane [94]
Potassium inward rectifier channel Kir2 (encoded
byKCNJ2) was responsible for terminal cardiac repolariza-
tion and resting membrane stability [97]. “Loss-of-
function”or “Gain-of-function”mutations of KCNJ2 gave
rise to atrial fibrillation. Kv 2.1 (encoded by KCNB1) could
be downregulated in myocardial infarction patients and lead
to electrical instability of the post-MI heart [98]. Matrine
(50, 100, and 200 mg/kg, intragastrically administrated for
seven days) [99] upregulated the expression of KCNB1
(encoding Kv 2.1) and KCNJ2 (encoding Kir2.1) in myocar-
dial tissues of rats with myocardial infarction and prevented
the occurrence of arrhythmia after myocardial infarction.
(2) Calcium Channel. Matrine (15, 30, and 45 mg/kg intrave-
nously administrated once a day for 15 days) upregulated
Cav1.2 expression on atrial membrane. It promoted the
increase of L-type calcium current and the recovery of
calcium-induced calcium release (CICR), which ultimately
improved myocardial contractility and cardiac function
and prevented heart failure in rats with AF [100]. Moreover,
matrine (100 mg/kg/d, intragastrically administrated for four
weeks) improved atrial fibrosis and reduced the susceptibil-
ity of AF in rats with myocardial infarction by inhibiting
the proliferation, migration, and differentiation of cardiac
fibroblasts [101].
(3) Sodium Channel. Voltage and concentration-depen-
dently, matrine inhibited sodium channels. In vitro, matrine
(10, 50, and 100 μmol/L) inhibited sodium current in rat’s
ventricular myocytes and reduced the action potential
amplitude (APA) [102, 103].
3.2.4. Dauricine (Dau). Dauricine is a kind of bibienyl
isoquinoline alkaloid extracted from the roots of Menisper-
mum dauricum DC., with antiarrhythmia [104], anti-
inflammatory [105], antitumor [106], and anticoagulation
[107] effects. In terms of antiarrhythmia, dauricine reduced
Ca2+ and Na+ influx and K+ outflow. Dauricin e (200 μg/
mL) [108] prolonged the atrial effective refractory period
and action potential duration and significantly inhibited
Na+, K+, and Ca2+ current in myocardial tissues.
(1) Potassium Channel. In guinea pig ventricular myocytes,
dauricine (1, 3, 10, 30, and100 μmol/L) inhibited the rapidly
and slowly activating component of the delayed rectifier
potassium current and the inward rectifier potassium cur-
rent [85]. Dau inhibited both active and inactive states of
HERG channels [109]. Unlike quinidine and dofetilide,
dauricine did not affect the deactivation process of Ikr and
Iks and was not likely to cause torsade de pointes ventricular
tachycardia [110].
(2) Calcium Channel. Dauricine was an L-type calcium
channel blocker that reduced intracellular Ca2+ concentra-
tion by inhibiting Ca2+-ATPase activity and sarcoplasmic
reticulum calcium uptake. In rabbit papillary cardiomyo-
cytes, dauricine (30 μmol/L) inhibited early depolarization
by inhibiting L-type calcium channels [111, 112]. Dauri-
cine’s inhibiting effects of Ca2+ channels were also associ-
ated with activated Na+-K+-ATPase and Ca2+-Mg2
+-ATPase [113].
(3) Connexin. Decreased expression or function of connexin
40 protein promoted the aggravation of paroxysmal atrial
fibrillation into persistent atrial fibrillation [114]. Dauricine
(intravenous injecting 5 mg/kg, 30 min before rapid atrial
pacing) inhibited the degradation of Cx40 and the damage
of atrial myocytes caused by rapid atrial pacing [115].
3.2.5. Guanfu Base A (GFA). Extracted from the roots of
Aconitum coreanum (Levl.) Rapaics of Ranunculaceae,
GFA has antiarrhythmia [116], anti-inflammatory [117],
and antioxidation [118] effects. At present, it has been
approved in the treatment of supraventricular tachycardia
in China. In terms of antiarrhythmia, GFA is a kind of
5Cardiovascular Therapeutics

multichannel blocker, which mainly blocks sodium chan-
nels. GFA can not only restrain action potential amplitude
(APA) and Vmax and prolong action potential duration
and effective refractory period but also change unidirectional
conduction block into bidirectional conduction block and
reduce the occurrence of premature contraction and atrio-
ventricular reentry [119, 120].
(1) Potassium Channel. GFA mainly inhibited slow-activated
delayed rectifier potassium current (Iks), with little influence
on rapid-activated delayed rectifier potassium current (Ikr)
[121]. Therefore, it was less likely to cause other arrhythmias
[122]. In a frequency-dependent manner, GFA (100, 400,
1000, and 2500 μmol/L) inhibited potassium currents by
binding to the S6 region of the HERG channel without
affecting the synthesis of HERG proteins. It inhibited the
expression of HERG proteins at high concentrations [123].
GFA did not affect the inward potassium current channel
and transient outward potassium current channel, so it
would not lead to early repolarization [124].
(2) Calcium Channel. By reducing Ca2+ influx, GFA reduced
the depolarization rate and average repolarization rate of
cardiomyocytes [125]. GFA mainly acted on the inactive
state of the L-type calcium channel, which prolonged recov-
ery time from the inactivation state. GFA also had a certain
effect on the calcium channel in the inactive state [126]. GFA
(25, 125, 250, and 1000 μmol/L) blocked L-type calcium
channel in rats’ventricular myocytes in a concentration-
dependent manner.
(3) Sodium Channel. By inhibiting the sodium channel, GFA
reduced the heterotopic automaticity of atrial and ventricu-
lar cells [117]. GFA not only reduced the occurrence of reen-
try by slowing down the atrioventricular bypass conduction
but also prolonged the action potential duration and effec-
tive refractory period. In vitro, GFA (500 μmol/L) reduced
the depolarization rate and average repolarization rate of
rabbits’sinus node cells [127].
In addition, GFA could inhibit the late sodium channel,
which was considered as a potential drug target of AF [128].
Late sodium current increased intracellular sodium and
calcium loading [98] and enhanced susceptibility to atrial
fibrillation [104], heart failure [129], and hypoxia [130].
Mutation in SCN5A (sodium voltage-gated channel alpha
subunit 5) gene increased late sodium current and gave rise
to malignant arrhythmia with pleomorphic ventricular
tachycardia and torsade de pointes (TdP). By inhibiting the
expression of the SCN5A, GFA (100 μmol/L) shortened the
recovery time of action potential and restrained the triggered
activity caused by early after depolarization and delayed
after depolarization [131].
(4) Connexin. GFA (6 and 12 mg/kg, intragastrically admin-
istrated for four days) shortened the duration of atrial fibril-
lation in calcium chlorine-acetylcholine model rats,
prolonged the effective refractory period, reduced the
expression of NADPH oxidase-related subunits, and pro-
moted the communication junction protein expression (con-
nexin 40). In this way, it inhibited atrial electrical
remodeling caused by atrial fibrillation and increased the
success rate of conversion to sinus rhythm.
In a clinical trial, 41 patients with atrioventricular reen-
trant tachycardia in the treatment group were intravenously
injected GFA (200 mg, if the first dose is ineffective, the sec-
ond dose may be given after 15 minutes), and 41 patients in
the control group intravenously were injected propafenone
hydrochloride (70 mg, intravenously injected, if the first dose
is ineffective, the second dose may be given after 30 minutes)
[132]. The results showed that the effective rate of GFA
hydrochloride in the treatment of atrioventricular reentrant
tachycardia was higher than that of propafenone hydrochlo-
ride (87.8% vs. 68.3%, P<0:05). The recovery time of collat-
eral retrograde transmission in the GFA group was longer
than that in the propafenone group (36:6±9:7vs. 19:2±
7:3min, P<0:05).
3.2.6. Neferine. Extracted from the seeds of lotus of Nym-
phaeaceae, neferine has antiarrhythmia, antihypertensive
[133], antitumor [134], antiapoptotic, antioxidative, [135],
anti-ischemic [136], antiallergic, and anti-inflammatory
effects [137]. In terms of arrhythmia, by reducing the Na+,
Ca2+ ion influx, and K+ outflow, nephrine can effectively
prolong the Q-T interphase and slow down heart rate [138].
(1) Potassium Channel. By blocking the HERG potassium
channel, neferine (10 and 30 μmol/L) inhibited potassium
outflow during repolarization, prolonged the action poten-
tial duration, and effective refractory period [116, 140]. In
vitro, neferine (10 and 100 μmol/L) reduced the peak value
of potassium current in rabbit ventricular myocytes by
56.96% and 73.61%, respectively [65].
(2) Calcium Channel. Concentration dependently, neferine
blocked the L-type calcium channel and had a synergistic
effect with verapamil. In vitro, neferine reduced the peak cal-
cium current of rabbit ventricular myocytes by 17.46% and
51.06% at concentrations of 10 and 100 μmol/L (Zuo et al.,
2021 [140]). Neferine inhibited intracellular calcium influx
induced by adenosine diphosphate (ADP) by inhibiting
Ca2+ influx and internal Ca2+ discharge [141].
(3) Sodium Channel. Neferine (30 μmol/L) inhibited activa-
tion of Nav1.5 currents in a frequency-dependent manner
[38] in HEK293 cells. Neferine (40 μmol/L) reduced the
action potential amplitude (APA), maximum rising rate
(Vmax), and maximum rate of depolarization in rats’
cardiomyocytes [142]. Neferine significantly inhibited the
function of the sinoatrial node and the conduction of electri-
cal current between atrial and ventricular cells [110].
3.3. Quinones
3.3.1. Tanshinone IIA. Extracted from the root of Salvia
miltiorrhiza Salvia miltiorrhiza Bunge., tanshinone?A has
anti-arrhythmic [143], anticoagulant, anti-ischemic [144],
6 Cardiovascular Therapeutics

anti-neoplastic [145], and anti-inflammatory [146] effects.
By inhibiting potassium and calcium ion channels, tanshi-
none IIA can prolong the effective refractory period and
action potential duration, inhibit cardiac repolarization,
and increase the threshold of ventricular fibrillation [147].
(1) Potassium Channel. The KCNJ2 gene that encoded
Kir2.1 and Kir2.2 proteins of inward rectifier potassium
channels [121] was associated with the pathogenesis of atrial
fibrillation [148]. KCNQ1 gene-encoded Kv7.1 protein of
Iks, while KCNE1 encoded Mink protein of Iks channel. In
myocytes of AF rats, tanshinone IIA upregulated the expres-
sion of KCNJ2, downregulated the expression of KCNQ1
and KCNE1, and inhibited myocardial cell potassium out-
flows and repolarization of cardiomyocytes [129, 149]. In
vivo, tanshinone IIA (2 mg/kg) significantly prolonged the
rabbit ventricular relative refractory period, effective refrac-
tory period [150]. Because of little impact on the Ikr channel,
tanshinone IIA was less arrhythmogenic than sotalol.
(2) Calcium Channel. Tanshinone IIA (32 mg/kg, intragastri-
cally administrated for 14 days) significantly upregulated the
expression of the CACNA1C gene in atrial tissue of AF rats
and improved atrial electrical remodeling and calcium over-
load [41]. Tanshinone IIA reduced the expression of
microRNA-1 through the p38 mitogen-activated protein
kinase pathway [129, 151]. In addition, tanshinone IIA
inhibited collagen secretion induced by AngII and the syn-
thesis rate of atrial fibroblasts by means of inhibiting the
TSP-1/TGF-β1 pathway [152]. The differentiation of atrial
fibroblasts into myofibroblasts plays an important role in
atrial fibrosis. As a water-soluble derivative of tanshinone
IIA, sodium tanshinone IIA sulfonate prevented atrial fibro-
sis by inhibiting oxidative stress and TGF-βactivation in the
AngII-1 signaling pathway [153].
In China, tanshinone IIA has been widely used in the
clinical treatment of myocardial infarction complicated by
atrial fibrillation. Wang and Xie [154] conducted a meta-
analysis that included ten clinical studies (involving 1088
patients). The results showed that success rate of conversion
into sinus rhythm (OR = 3:10, 95%CI = 2:16-4.44, P<0:05),
the recurrence rate of atrial fibrillation (OR = 0:32,
95%CI = 0:22-0.48, P<0:05), the incidence rate of heart fail-
ure (OR = 0:23, 95%CI-0.15-0.35, P<0:05), mortality
(OR = 0:23,95%CI = 0:15-0.35, P<0:05), and adverse reac-
tion rate (OR = 0:24, 95%CI = 0:12-0.49, P<0:05) in the
treatment group (Tanshinone IIA sulfonate combined with
amiodarone) were better than those in the control group
(only amiodarone).
3.4. Polyphenols. Polyphenols are secondary metabolites with
polyatomic phenol structures that are widely found in the
skin, roots, leaves, and fruits of medicinal plants like Polyg-
onum cuspidatum Sieb.et Zucc., Syringa oblata Lindl., and
Paeonia suffruticosa Andr. Among them, resveratrol, puer-
arin, and acacetin have been found with good antiarrhyth-
mic effects.
3.4.1. Resveratrol. Extracted from dry roots of Polygonum
cuspidatum Sieb.et Zucc. of Polygonaceae, resveratrol has
antiarrhythmia [155], antioxidation [156], antitumor [157],
anti-ischemic [158], and antiplatelet [159] effects. In terms
of antiarrhythmic, resveratrol can slow down the heart rate,
prolong the effective refractory period of cardiomyocytes,
and inhibit the occurrence of early and delayed after depo-
larization [158], by regulating potassium, calcium, and
sodium ion channels [160].
(1) Potassium Channel. Resveratrol prolonged action poten-
tial duration and effective refractory period by inhibiting the
expression of the HERG gene, as well as rapid and slow acti-
vation of delayed rectifying potassium ion current [161]. In
vitro, resveratrol (50, 100, and 500 μM) slowed down guinea
pigs’heart rate and inhibited myocardial contractility in a
dosage-dependent manner by regulating ATP-sensitive
potassium channels, transient outward potassium current,
calcium-activated potassium channels, and inward rectifying
potassium channels [162].
Resveratrol enhanced Kv2.1 potassium current in H9C2-
rat cardiomyocytes in a time- and concentration-dependent
manner. The median maximum effective concentration was
14.02 μmol/L [163].
(2) Calcium Channel. Resveratrol (1, 50, and 100 μmol/L)
inhibited the L-type calcium channel, reduced the intracellu-
lar calcium influx, and prolonged the effective refractory
period in guinea pig ventricular myocytes [164, 165]. Resver-
atrol not only inhibited the occurrence of early and delayed
after depolarization (EAD and DAD) but also slowed down
the atrioventricular conduction and inhibited atrioventricu-
lar node reentry excitement. In vitro, resveratrol protected
guinea pigs’ventricular myocytes from oxidative stress-
induced arrhythmias and calcium overload, by means of
inhibiting L-type calcium channel, reducing the production
of oxygen free radicals in cardiomyocytes, and preventing
the activation of calmodulin-activated protein kinase II
(CaMK II) [155].
(3) Sodium Channel. Concentration-dependently, resveratrol
(10, 30, and 100 μmol/L) inhibited the late sodium current
and the reverse type sodium-calcium exchangers of ventric-
ular myocyte of guinea pig [166]. At the concentration of
100 μmol/L, resveratrol could inhibit 52:7±10:2%of
sodium current [167]. Resveratrol (10, 20, 40, and 80 μM)
inhibited ischemic arrhythmias by inhibiting the H2O2-
induced late sodium current and the reverse sodium-
calcium exchange current (INCX) [168].
(4) Connexin 43. Resveratrol could regulate the expression of
the GJA gene and myocardial connexin 43 (Cx43), which
play a therapeutic role in idiopathic atrial fibrillation [169].
Resveratrol (1 mL/kg, intravenous ly administered) upregu-
lated the expression and activity of Cx43 in male SD rats
by activating the PI3K/Akt signaling pathway, thus prevent-
ing myocardial ischemia-reperfusion arrhythmia [170]. Res-
veratrol (2.5 mg/kg/d, intragastrically administrated for
7Cardiovascular Therapeutics

seven days) inhibited atrial remodeling and reduced AF by
increasing activity of deacetylase 1 (SIRT1) [171].
(5) HCN Channel. Resveratrol inhibited hyperpolarization-
activated cyclic nucleotide-gated cation channel 4 (HCN4)
(IC50 value = 83:75 μmol/L) [172]. Resveratrol inhibited
Kv1.5 current and IKAch [173] frequency-dependently, with
IC₅₀ of 0.36 and 1.9 μmol/L [173].
3.4.2. Puerarin. Extracted from the dry root of Pueraria
puerariae, puerarin is a kind of flavonoid compound with
antiarrhythmia [175], anti-ischemic [176], antihypertensive
[177], hypolipidemic [178], hypoglycemic [179], coronary
vasodilation [180], and anti-inflammatory [181] effects. In
China, puerarin (Yufeng Ningxin Dropping Pill) has been
approved for the clinical treatment of hypertension, coro-
nary heart disease, angina pectoris, and neuropathic head-
ache. In terms of antiarrhythmia, puerarin can slow down
the heart rate, inhibit the cardiomyocyte automaticity, pro-
long the effective refractory period, and action potential
duration [182, 183].
(1) Potassium Channel. Puerarin (0.01, 0.1, and 1 mmol/L)
prolonged the duration of the action potential by inhibiting
IKs in rat ventricular myocytes [184]. Zhang et al. [185]
found that puerarin was a novel antagonist towards inward
rectifier potassium channel (IK1). Puerarin (1.2 mmol/L)
significantly inhibited the IK1 current in rat ventricular cells.
In the transfected HEK293 cells, puerarin significantly
inhibited inward rectifying K+ channels in a dose-
dependent manner and had a more significant effect on
Kir2.1 and Kir2.3. Puerarin significantly inhibited Kv7.1
and IKs in micromolar concentrations [186]. Moreover, by
regulating the calcium-activated potassium channel and
activating protein kinase C, puera rin (0.24 mmol/L) pro-
tected rats’ventricular myocytes against ischemia and reper-
fusion injury [187].
(2) Calcium Channel. Puerarin (2.4 mmol/L) inhibited the L-
type calcium channel in rats’ventricular myocytes in a time-
dependent manner [188]. Puerarin (100 mg/kg, iv) [189] sig-
nificantly inhibited the arrhythmias (including ventricular
premature contraction, ventricular tachycardia, and ventric-
ular fibrillation) induced by chloroform (2 mL inhaled by
mice) or aconitine (40 mg/L intravenous injected to SD rats).
Puerarin ([190], 100 mg/kg intraper itoneally injected for ten
days) inhibited isoproterenol-induced cardiac hypertrophy
and reduced intracellular calcium concentration.
(3) Sodium Channel. M. Puerarin inhibited sodium channels
in a dose-dependent manner with IC ð50Þ= 349 μmol/L
[191]. Wang conducted a prospective cohort study involving
87 patients with persistent atrial fibrillation. Forty-three
patients in the control group received amiodarone (0.2 g
tid for one week, 0.2 g, bid for one week, and 0.2 g QD for
the last week); 44 patients in the combination group received
puerarin (40 mL + 250 mL 0.9% NaCl, ivgtt, for 21 days)
based on the control group. The results showed that the
average time of restoring sinus rhythm in the combination
group was significantly shorter than that of the control
group (7.5 d vs. 10.2 d, P<0:01), and the success rate of
restoring sinus rhythm was significantly higher than that of
the control group (77.3% vs. 60.5%, P<0:01)[192].
3.4.3. Acacetin. Acacetin is a kind of flavonoid extracted from
Saussurea involucrata (Kar. et Kir.) Sch.-Bip., with antiar-
rhythmic [193], antitumor [194, 195], anti-inflammatory
[196], antifibrosis [197], and antioxidation [198]. In terms
of antiarrhythmia, acacetin is a kind of potassium channel
inhibitor without effect on the Na(+) and L-type Ca (2+)
channels. Acacetin (3, 6, and 12 mg/kg, intravenously admin-
istrated for seven days) terminated experimental AF of beagle
dogs without prolonging QTc interval [199].
(1) Potassium Channel. Acacetin (5–10 μM) reduced Ito
density, action potential notch, and J wave area in electrocar-
diograph [200]. Encoded by KCNA5, ultrarapid delayed
rectifier potassium channel (Kv1.5) was only expressed in
human atrial myocytes. Inhibiting the Kv1.5 current could
prolong atrial action potential duration and increase the
refractory period of the fibrillating atrium [14]. Acacetin
(IC50 = 3:2and 9.2 μmol/L, respectively) inhibited ultra-
rapid delayed rectifier potassium current I (Kur) and the
transient outward K+ current and IKACh in human atrial
myocytes [201], with little potency in inhibiting IKr and
IKs. Other flavonoids, including hesperetin [14], myricetin
[202], and quercetin [203], could also inhibit I (Kur).
Blocking the K+ channel could enhance the AF-
selectivity of INa blockade. As a K+-current blocker, acacetin
combined with INa blocker showed synergistic antiarrhyth-
mic benefits without significant alterations of ventricular
repolarization and QT intervals.
Acacetin showed a weak inhibition in the hERG and
KCNQ1/KCNE1 channels [193] in rabbit hearts. In cardio-
myocytes of anesthetized dogs, acacetin (2.5, 5, and 10 mg/
kg) prevented AF induction [193]. Chen et al. [204] found
that acacetin inhibited small conductance Ca2+-activated K
+ channel (SKCa) currents with IC50 of 12.4 μM for SKCa1,
10.8 μM for SKCa2, and 11.6 μM for SKCa3.
3.5. Organic Acid. Organic acids are organic compounds
with acidity that are widely distributed in leaves, roots,
and fruits of Chinese Materia Medica like Glycyrrhiza
uralensis Fisch.
3.5.1. Glycyrrhizic Acid (GA). Extracted from the dried root
and rhizome of Glycyrrhiza uralensis Fisch., Glycyrrhiza
inflata Bat., or Glycyrrhiza glabra L., glycyrrhizic acid has
antiarrhythmia [205], antioxidant, anti-inflammatory [206],
antiviral [181], and antitumor (Zuo et al., 2021) effects
[207]. In terms of arrhythmia, glycyrrhizic acid can block
sodium and calcium ion channels to inhibit the automaticity
of pacemaker cells, slow down the conduction speed,
prolong the action potential duration, and effective refrac-
tory period [208].
8 Cardiovascular Therapeutics

Table 1: The effects of active components of antiarrhythmic natural products exerted on ion channels.
Origin Names Pharmacological
action Chemical structure Potassium channel Calcium
channels
Sodium
channel Connexin HCN
Panax
notoginseng
(Burk.) F.H.
Chen
Panax
notoginseng
saponins
Antiarrhythmia [42],
antiplatelet [37],
antishock [39],
antioxidation [225],
sedative [40], and
antitumor [41]
R3O
R1O
R2
OH
Small conductance
calcium activates
potassium channel,
potassium calcium-
activated channel
[43]
L-type and
T-type Ca2+
channel [44]
[50]
Coptis
chinensis
Franch.,
Phellodendron
chinense
Schneid,
Mahonia
bealei (Fort.)
Carr
Berberine
Antiarrhythmia [54],
anti-inflammatory
[55], antibacterial
[56], hypoglycemia
[57], vasodilation
[58], antitumor
effects [59].
O
O
O
O
N+
Delayed rectifier
outward potassium
channel, ATP-
sensitive K+ (KATP)
channels, inward
rectifier potassium
channel ([64, 65])
L-type and
T-type
calcium
channel,
ryanodine
receptor,
sarcoplasmic/
endoplasmic
reticulum
calcium
ATPase
([66]; [67])
[68]
hHCN4 [70]
Stephania
tetrandra S.
Moore.
Tetrandrine
Antiarrhythmia [73],
antihypertensive
[74], anti-
inflammatory [75],
and antitumor [74]
OO
O
O
O
NN
O
Delayed rectifier
potassium channel,
calcium-activated
potassium channel
[18]
L-type and
T-type
calcium
channels,
sarcoplasmic/
endoplasmic
reticulum
calcium
ATPase [80]
[82]
Voltage-
gated
cardiac
sodium
channel
[22] [84]
Sophora
alopecuroides
L., Sophora
flavescens Alt.
Matrine
Antiarrhythmia [85],
antibacterial [226],
antipulmonary [86],
and hepatic fibrosis
[87], and antitumor
[88]
N
N
ODelayed rectifier
potassium channel,
M3 receptor-
mediated K+
channel [96] [94],
potassium inward
rectifier channel [98]
[99]
L-type
calcium
channels
[100] [101]
Voltage-
gated
cardiac
sodium
channel
([103];
[102])
9Cardiovascular Therapeutics

Table 1: Continued.
Origin Names Pharmacological
action Chemical structure Potassium channel Calcium
channels
Sodium
channel Connexin HCN
Menispermum
dauricum DC.Dauricine
Antiarrhythmia
[104], anti-
inflammatory [105],
antitumor [106],
anticoagulation
[107]
O
OOH
O
O
O
N
N
Delayed rectifier
potassium channel,
inward rectifier
potassium channel
[94] [95] [96]
L-type
calcium
channels
[101] [100]
Cx40
([27]; [28])
[29] [30]
[31] [115]
Aconitum
coreanum
(Levl.) Rapaics
Guanfu base
A
Antiarrhythmia
[116], anti-
inflammatory [117],
and antioxidation
[118]
O
O
N
O
O
HO
OH
Delayed rectifier
potassium channel
[121] [122] [124]
L-type
calcium [125]
[126]
Voltage-
gated
cardiac
sodium
channel
[117] [127]
Cx40 [132]
Lotus of
Nymphaeaceae Neferine
Antiarrhythmia,
antihypertensive
[133], antitumor
[134], antiapoptotic
and antioxidative
[135], anti-ischemic
[136], antiallergic,
and anti-
inflammatory
effects[137]
O
O
N
O
N
O
HO
O
HERG potassium
channel ([116];
[140])
L-type
calcium
channel (Zuo
et al., 2021)
[141]
Voltage-
gated
cardiac
sodium
channel
[38] [142]
[110]
10 Cardiovascular Therapeutics

Table 1: Continued.
Origin Names Pharmacological
action Chemical structure Potassium channel Calcium
channels
Sodium
channel Connexin HCN
Salvia
miltiorrhiza
Bge.
Tanshinone
IIA
Antiarrhythmic
[143],
anticoagulation,
anti-ischemia [144],
antitumor [145], and
anti-inflammation
[146]
O
OO
Delayed rectifier
potassium channel
([129]; [149]),
inward rectifier
potassium channel
[227] [148]
type calcium
channel [41]
Voltage-
gated
cardiac
sodium
channel
[152]
Vitis vinifera
L., Punica
granatum L.,
Vaccinium
spp.,
Vaccinium
macrocarpon
Resveratrol
Antiarrhythmia
[155], antioxidation
[156], antitumor
[157],
antimyocardial
ischemia [158], and
antiplatelet [159]
HO
HO
OH Delayed rectifier
potassium channel
[161], ATP-sensitive
potassium channels,
transient outward
potassium channel,
calcium-activated
potassium channel,
and inward
rectifying potassium
channel [163]
L-type
calcium
([164]; [165])
[155]
Late
sodium
channel
and reverse
type
sodium-
calcium
exchangers
[166]
Cx43 [169]
[170]
Hyperpolarization-
activated cyclic
nucleotide-gated
cation channel
[172] [173]
Pueraria
lobata (Willd)
Ohwi,
Pueraria
thunbergiana
Benth.
Puerarin
Antiarrhythmia
(Wei et al., 2015
[175]), anti-ischemic
[176],
antihypertensive
[177], lowering
blood lipid [178],
lowering blood sugar
[179], expanding
coronary arteries
[228], and anti-
inflammatory [181]
HO
HO
HO
O
O
O
OH
OH
OH
Delayed rectifier
potassium channel,
inward rectifier
potassium channel
[185] [186], calcium-
activated potassium
channel [187]
L-type
calcium [188]
Voltage-
gated
cardiac
sodium
channel
[191]
Saussurea
involucrata
(Kar. et Kir.)
Sch.-Bip.
Acacetin
Antiarrhythmic
[193], antitumor,
anti-inflammatory,
antifibrosis,
antioxidation [198]
HO
HO
O
O
O
Ultrarapid delayed
rectifier potassium
channel and the
transient outward
potassium channel
[193], hERG, small
conductance Ca2
+-activated K+
channels [204],
transient outward
potassium channel
[200]
11Cardiovascular Therapeutics

Table 1: Continued.
Origin Names Pharmacological
action Chemical structure Potassium channel Calcium
channels
Sodium
channel Connexin HCN
Glycyrrhiza
uralensis
Fisch.,
Glycyrrhiza
inflata Bat., or
Glycyrrhiza
glabra L.
Glycyrrhizic
acid
Antiarrhythmia
[205], antioxidant,
anti-inflammatory
[206], antiviral
[229], antitumor
(Zuo et al., 2021)
O
OH
HO
HO
HO
HO
HO
OH
OH
O
O
O
O
O
O
O
L-type
calcium
channel
[205]
Voltage-
gated
cardiac
sodium
channel
[210] [211]
Artemisia
carvifolia
Buch.-Ham. ex
Roxb. Hort.
Beng.
Artemisinin
Antimalarial [212],
antitumor [213],
anti-inflammatory
[214], antiviral
[215], antibacterial
[216], and
antifibrotic [217]
O
O
O
O
O
Delayed rectifier
potassium channel,
inward rectifier
potassium channel,
transient outward
channel [218] [219]
L-type
calcium
channel
[220]
Cx43[221]
[222]
Hyperpolarization-
activated cyclic
nucleotide-gated
cation channel
[223]
12 Cardiovascular Therapeutics

(1) Calcium Channel. Glycyrrhizic acid can act on the CAC-
NA1C gene to inhibit the L-type Ca2+ channel current in
cardiomyocytes. Therefore, it can hinder sinus node pacing
early and delayed depolarizing triggering activities [205].
Adrenergic receptors of the heart stimulated by epineph-
rine and norepinephrine can promote the release of cAMP,
phosphoinositide, and the second messenger signaling cas-
cade [209]. In vitro, ten μM GA can inhibit the cAMP levels
of CHO cells transfected with β2-AR or β3-AR, suggesting
its’selective antagonistic capability against β2-AR and β3-
AR [205].
(2) Sodium Channel. Glycyrrhizic acid can inhibit sodium
ion channels in cardiomyocytes in a concentration-
dependent manner [210]. Glycyrrhizic acid can inhibit Na
+influx of cardiac myocytes during depolarization, reduce
action potential amplitude and maximum rise rate of the
action potential, slow down conduction velocity, and reduce
Na + influx in phase 4 of action potential duration in ectopic
pacemaker cells, thus decreasing the excitability of ectopic
pacers [211].
3.6. Terpenoids. Widely existing in natural products, terpe-
noids are compounds and derivatives derived from methyl
glutaric acid and whose molecular skeleton takes isoprene
unit as the basic structural unit.
3.6.1. Artemisinin. Extracted from Artemisia annua L., arte-
misinin has antimalarial [212], antitumor [213], anti-
inflammatory [214], antiviral [215], antibacterial [216], and
antifibrotic [217] effects. Artemisinin (5, 10, and 20 mg/kg,
intraperitoneally injected for once) inhibited arrhythmia
induced by barium chloride by regulating sympathetic tone.
Artemisinin was superior to amiodarone in prolonging QT
interval (4.0 mg/kg, intraperitoneally injected), and there
were fewer adverse reactions [180].
(1) Potassium Channel. Artemisinin (5 and 50 μmol/L) inhib-
ited the inward rectifier potassium channel (IK1) of African
frog [218] and inhibited IK1, It0, and delayed activation recti-
fier potassium current of dogs’cardiomyocytes [219].
(2) Calcium Channel. Artemisinin (4, 2, and 1 mg intragas-
trically administrated for 28 days) upregulated Cav1.2
calcium channel expression level, downregulated the expres-
sion level of calmodulin and calmodulin-dependent protein
kinase II (CaMKII), and inhibited the level of phosphory-
lated ryanodine receptor 2 [220].
(3) Connexin 43. Cx43 remodeling was associated with
action potential duration dispersion and reducing conduc-
tion [221]. Artemisinin increased Cx43 expression by
inhibiting TNF-αand attenuating sympathetic tone [222].
(4) Hyperpolarization-Activated Cyclic Nucleotide-Gated
Cation Channel (HCN). HCN mainly had the following
characteristics: activated by hyperpolarization, sodium-
potassium ion mixed channel, double regulated by voltage,
and cyclic nucleotide [223]. HCN channel was the primary
determinant of phase 4 automatic depolarization of auto-
rhythmic cells and improved the autonomy of autorhythmic
Matrine PNS PNS
Berberine
Berberine
Tetrandrine
PNS
ATP2A2
HCN
RyR2
Berberine
Berberine
Tetrandrine
PNS
Berberine
Tetrandrine
Matrine
Guanfu
base A
Berberine
Tetrandrine
Guanfu base
A
Guanfu base A
Dauricine
Dauricine
TanshinoneIIA
TanshinoneIIA
TanshinoneIIA
Resveratrol
Resveratrol
Resveratrol
Resveratrol
Resveratrol
Puerarin
Puerarin
Puerarin
Artemisinin
Artemisinin
Berberine
Tetrandrine
Tetrandrine
Matrine
Matrine
Dauricine
Artemisinin
Artemisinin
Artemisinin
Neferine
Neferine
Neferine
Glycyrrhizic
acid
Glycyrrhizic
acid
IKs
IKr
IK
IK Ach
INa
IK ATP IKM3 ISK
ICa, T
ICa, L
Figure 2: Natural products’effects on potassium, sodium, and calcium channels.
13Cardiovascular Therapeutics

cells. Artemisinin (75 mg/kg, intragastrically administrated,
three times a day for four weeks) inhibited the pacing cur-
rent of sinoatrial node in rabbits with heart failure, reduced
the expression of HCN channel, and thus reduced the heart
rate [224].
4. Summary
Based on the classification of chemistry structure, the effects
of saponins, alkaloids, polyphenols’effects on potassium,
sodium, and calcium channels of cardiomyocytes are
summarized in this article (see Table 1 and Figure 2). In
addition, the natural products’regulatory effects exerted on
the expression level and function of genes responsible for encod-
ing ion channel protein are also summarized (see Table 2).
However, most of the studies above are limited to animal
or cell experiments, which only preliminarily demonstrate
their therapeutic effect on atrial fibrillation. In the future,
studies on pharmacokinetics/pharmacodynamics and mech-
anisms as well as clinical trials of natural products with anti-
arrhythmic activity should be performed. We will continue
to track relevant reports to promote the development of
new AADs.
5. Conclusion
Potassium, calcium, sodium channel, connexins, and HCN
channel are involved in the pathogenesis of atrial fibrillation.
In terms of potassium channels, predominantly expressed in
atria, ultrarapidly delayed rectifier potassium channel (Kur)
and small conductance calcium-activated potassium channel
(SKCa) can be considered to be atrial-selective targets for
developing anti-AF drugs. Kur can enhance spiral-wave
reentry. SKCa can prolong atrial repolarization in the
pulmonary vein and inhibit the maintenance of atrial fibril-
lation. Ectopic rhythm caused by EAD, DAD, and calcium
overload can be inhibited by blocking L-type calcium chan-
nels or late sodium channels. Increasing the expression or
function of connexins can inhibit reentry and heterogeneous
conduction. HCN channel is a promising channel in heart
rate control therapy by inhibiting diastolic depolarization.
Tanshinone IIA and Guanfu A have been approved in
the clinical treatment of arrhythmia in China. The advantage
of tanshinone IIA is inhibiting structural and electrical
remodeling. The benefit of Guanfu A is inhibiting triggered
activity and atrioventricular reentry. Although PNS, berber-
ine, and puerarin have been found effective in clinical trials
of paroxysmal atrial fibrillation, their efficacy still needs to
be confirmed by well-designed, randomized, double-blind
controlled trials.
Abbreviations
AAD: Antiarrhythmic drugs
CNKI: Chinese National Knowledge Infrastructure
AF: Atrial fibrillation
NICE: National Institute for Health and Care
Excellence
AHA: American Heart Association
ACC: American College of Cardiology
HRS: Heart Rhythm Society
EACTS: European Association of Cardio-Thoracic
Surgery
KCNA5: Potassium voltage-gated channel subfamily A
member 5
KCNN3: Potassium calcium-activated channel subfam-
ily N member 3
miR-499: MicroRNA-499
Table 2: Natural product active components’regulatory effects on the genes responsible for ion channel proteins.
Gene Encoding protein Upregulate Downregulate
SCN5A Nav1.5 GFA
KCNB1 Kv2.1 Matrine
KCND3 Kv4.3 PNS
KCNE1 Mink Tanshinone IIA
KCNH2 Kv11.1 Matrine Berberine, matrine,
resveratrol
KCNJ2 Kir2.1 Matrine, tanshinone IIA
KCNQ1 Kv7.1 Tanshinone IIA
KCNN3 KCa2.3 PNS
hHCN4 Hyperpolarization-activated cyclic nucleotide gated potassium
channel Berberine
SK3 Small conductance calcium activates potassium channel 3 PNS
CACNA1C Cav1. 2 Matrine, Tanshinone
IIA PNS
CACNB1 Calcium voltage-gated channel auxiliary subunit beta PNS
RyR2 Ryanodine receptor Berberine
GJA1 Gap junction protein 43 (Cx43) Resveratrol
GJA5 Gap junction protein 40 (Cx40) GFA, puerarin
ATP2A2 ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporter PNS, berberine
14 Cardiovascular Therapeutics

miR-29: MicroRNA-29
IKr: Delayed rapid-rectifying potassium current
IKM
3
: M3 receptor-mediated K
+
current
CICR: Calcium-induced calcium release
SCN5A: Sodium voltage-gated channel alpha subunit 5
KCNB1: Potassium voltage-gated channel subfamily B
member 1
PI3K: Phosphatidylinositol 3 kinase
KCNE1: Potassium voltage-gated channel subfamily E
member 1
CACNB1: Calcium voltage-gated channel auxiliary sub-
unit beta 1
GJA1: Gap junction protein alpha 1
GFA: Guanfu base A
Iks: Slow activated delayed rectified potassium
current
KCNQ1: Potassium voltage-gated channel subfamily Q
member 1
TGF-β1: Transforming growth factor beta 1
INCX: Reverse sodium-calcium exchange current
CaM: Calmodulin
IK1: Inward rectifier potassium channel
RyR2: Ryanodine receptor2
SERCA2: Sarcoplasmic reticular Ca
2+
-ATPase
KCNE1: Potassium calcium-activated channel subfam-
ily E member 1
KCNE3: Potassium calcium-activated channel subfam-
ily E member 3
HCN2: Hyperpolarization-activated cation channel 2
KChIP2: Potassium channel interacting protein 2
PNS: Panax notoginseng saponins
APD: Action potential duration
ERP: Effective refractory period
SK3: Small conductance calcium activates potas-
sium channel 3
ATP2A2: ATPase sarcoplasmic/endoplasmic reticulum
Ca
2+
receptor 2
HERG: Human ether-a-go-go-related gene
hHCN4: Hyperpolarization-activated cyclic nucleotide-
gated 4
APA: Action potential amplitude
KCNH2: Potassium voltage-gated channel subfamily H
member 2
KCND3: Potassium voltage-gated channel subfamily D
member 3
KCNJ2: Potassium voltage-gated channel subfamily J
member 2
KCNQ1: Potassium voltage-gated channel subfamily Q
member 1
CACNA1C: Calcium voltage-gated channel subunit alpha1 C
RyR2: Ryanodine receptor 2
GJA5: Gap junction protein alpha 5
Dau: Dauricine
Ikr: Rapid activated delayed rectified potassium
current
TSP-1: Thrombospondin-1
Ang II: Angiotensin II
CaMK II: Calmodulin-activated protein kinase II
Cx43: Connexin 43
SIRT1: Sirtuin 1.
Data Availability
The data used to support the findings in this study are
included within the article.
Disclosure
No funder support was involved in the manuscript writing,
editing, approval, or decision to publish.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Authors’Contributions
Jinshan He and Sicong Li contributed equally to this arti-
cle. They are both responsible for the initial outline, draft
writing, revisions, and final approval. Yumeng Ding was
responsible for English translation, presentation, draft
writing, and revisions for intellectual content. Xuebin Li
was the corresponding author and responsible for revi-
sions for intellectual content and final approval. Jinshan
He and Sicong Li contributed equally to this work.
Acknowledgments
The authors would like to thank all the scholars who have
made outstanding contributions to natural products.
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