Icariin, a Novel Blocker of Sodium and Calcium Channels, Eliminates Early and Delayed Afterdepolarizations, As Well As Triggered Activity, in Rabbit Cardiomyocytes

摘要

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 (APD_(50) and APD_(90)) and reduced AP amplitude (APA) and the maximum upstroke velocity (V_(max)) 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 ([Ca~(2+)]_(o), 3.6 mM) in LVMs. Icariin also decreased I_(NaT) in a concentration-dependent manner in LAMs and LVMs, with IC_(50) 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 I_(NaL) in a concentration-dependent manner in LVMs. Furthermore, icariin attenuated I_(CaL) in a dose-dependent manner in LVMs. The corresponding IC_(50) 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 I_(CaL) in LAMs (13.43 ± 2.73 μM; n = 9 cells/5 rabbits). Icariin induced leftward shifts in the steady-state inactivation curves of I_(NaT) and I_(CaL) in LAMs and LVMs but did not have a significant effect on their activation processes. Moreover, icariin had no effects on I_(K1) and I_(Kr) in LVMs or I_(to) and I_(Kur) in LAMs. These results revealed for the first time that icariin is a multichannel blocker that affects I_(NaT), I_(NaL) and I_(CaL) 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.