Abstract
Icariin, a flavonoid monomer from Herba Epimedii, has confirmed pharmacological and biological effects. However, its effects on arrhythmias and cardiac electrophysiology remain unclear. Here we investigate the effects of icariin on ion currents and action potentials (APs) in the rabbit myocardium. Furthermore, the effects of icariin on aconitine-induced arrhythmias were assessed in whole rabbits. Ion currents and APs were recorded in voltage-clamp and current-clamp mode in rabbit left ventricular myocytes (LVMs) and left atrial myocytes (LAMs), respectively. Icariin significantly shortened action potential durations (APDs) at 50 and 90% repolarization (APD50 and APD90) and reduced AP amplitude (APA) and the maximum upstroke velocity (Vmax) of APs in LAMs and LVMs; however, icariin had no effect on resting membrane potential (RMP) in these cells. Icariin decreased the rate-dependence of the APD and completely abolished anemonia toxin II (ATX-II)-induced early afterdepolarizations (EADs). Moreover, icariin significantly suppressed delayed afterdepolarizations (DADs) and triggered activities (TAs) elicited by isoproterenol (ISO, 1 μM) and high extracellular calcium concentrations ([Ca2+]o, 3.6 mM) in LVMs. Icariin also decreased INaT in a concentration-dependent manner in LAMs and LVMs, with IC50 values of 12.28 ± 0.29 μM (n = 8 cells/4 rabbits) and 11.83 ± 0.92 μM (n = 10 cells/6 rabbits; p > 0.05 vs. LAMs), respectively, and reversed ATX-II-induced INaL in a concentration-dependent manner in LVMs. Furthermore, icariin attenuated ICaL in a dose-dependent manner in LVMs. The corresponding IC50 value was 4.78 ± 0.89 μM (n = 8 cells/4 rabbits), indicating that the aforementioned current in LVMs was 2.8-fold more sensitive to icariin than ICaL in LAMs (13.43 ± 2.73 μM; n = 9 cells/5 rabbits). Icariin induced leftward shifts in the steady-state inactivation curves of INaT and ICaL in LAMs and LVMs but did not have a significant effect on their activation processes. Moreover, icariin had no effects on IK1 and IKr in LVMs or Ito and IKur in LAMs. These results revealed for the first time that icariin is a multichannel blocker that affects INaT, INaL and ICaL in the myocardium and that the drug had significant inhibitory effects on aconitine-induced arrhythmias in whole rabbits. Therefore, icariin has potential as a class I and IV antiarrhythmic drug.
Highlights
Icariin (C33H40O15, molecular weight = 676.7), the chemical structure of which has been reported by Tao et al (2013), is a flavonoid monomer extracted from Herba Epimedii
The main findings of the present study are as follows: (I) icariin reduced AP amplitude (APA) and maximum upstroke velocity of AP (Vmax) of action potential (AP), shortened action potential duration (APD) (APD50and APD at and 90% repolarization (APD90)) in left ventricular myocyte (LVM) and left atrial myocyte (LAM) (Table 1, Figure 1B). (II) Icariin decreased the rate dependence of the APD (RD) of APD (Figures 1C,D) and significantly suppressed early afterdepolarization (EAD) and delayed afterdepolarization (DAD) and triggered activity (TA) induced by anemonia toxin II (ATX-II) or ISO and high [extracellular calcium concentration (Ca2+]o), respectively, in LVMs (Figure 2). (III) Icariin decreased transient sodium current (INaT) in LVMs and LAMs (Figure 3) and attenuated the increases in late sodium current (INaL) induced by ATX-II in a concentration dependent manner in LVMs (Figure 4). (IV) Icariin blocked L-type calcium current (ICaL) in a dose-dependent manner in LVMs and LAMs (Figure 5)
reverse rate dependence (RRD) of APD enhancement leads to an increase in the cardiac transmural dispersion of the repolarization (Osadchii, 2013), which subsequently facilitates the occurrence of reentrant arrhythmias (Coronel et al, 2009; Maoz et al, 2014)
Summary
It was recently reported that icariin protected H9c2 cells from apoptosis by inhibiting endoplasmic reticular stress and the reactive oxygen speciesdependent JNK and p38 pathways (Zhang et al, 2013; Zhou et al, 2014). Sun et al (2011) found that icariin facilitated the differentiation of mouse embryonic cells into cardiomyocytes. The results of these studies indicate that icariin has cardioprotective effects. The effects of icariin on APs and ion channels in cardiomyocytes have not been reported. The aim of the present study was to investigate the effects of icariin on action potentials (APs), ion currents in cardiomyocytes, as well as arrhythmias in whole rabbits, and to further investigate the medicinal value of icariin for the treatment of heart diseases
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