Inhibitory Effects Of Artemisinin On Human HCN Channels Expressed Heterologously In Xenopus Oocytes

Artemisinin,an endoperoxide-containing sesquiterpene purified from the Chinese herbal plant Artemisia,or sweet wormwood,has been widely used as an effective antimalarial agent for several centuries.Its pharmacology and toxicology has been widely studied.With its established safety record in millions of malarial patients,artemisinins are also being investigated in diseases like infections,cancers and inflammation,autoimmune diseases,leukemia,arrhythmia,local anaesthesia.Artemisinin could block delayed outward rectified K+ current,affect the voltage-dependant Ca2+ channel in ventricular myocytes and improve the activity of ion channel.The effect of artemisinin on antiarrhythmic actions might result from its inhibition of voltage-gated Na+ channels,inward rectifier potassium currents and Ca2+ channels in a concentration-and time-dependent manner.It was suggesting that artemisinin is directly involved in the inhibition of action potential repolarization and depolarization,but the mechanism of this action has not been elucidated.Pacemaker channels(funny channels)are encoded by the hyperpolarization-activated cyclic nucleotide-gated(HCN)gene family.If current carries Na+(mainly),K+ and Ca3+(its molecuilar significance is unclear).Upregulation of the If and mRNA of HCN has been demonstrated in a variety of animal models of cardiac hypertrophy.In addition,Stillitano et al reported that both the mRNA and protein levels of HCN2 and HCN4 channels were increased several-fold in the atrium and ventricle of failing human hearts.Increased If densities strongly raise the tendency of ventricular muscle to develop ectopic,"pacemaker-like" action potentials,which contribute to arrhythmia.It was speculated that If overexpression in diseased states might play a critical role in arrhythmogenesis.There has no clinical reports verifying the effect of artemisinin on HCN channels.In this study,human HCN1,2 and 4 channels were expressed heterologously in Xenopus oocytes.The effects of artemisinin on the hHCN channels expressed in Xenopus oocytes were investigated using the microelectrode voltage clamp technique.We demonstrated that artemisinin reduced the current of hHCN channels expressed in Xenopus oocytes in a concentration-dependent and use-dependent manner.Its electropharmacological properties were shown to be consistent with those of an open-state blocker.In conclusion,artemisinin effectively inhibits hHCN channels in Xenopus oocytes,and the mechanism of its antiarrhythmic action may be related to its inhibition of the If current.