title: Effect of daurisoline on HERG channel electrophysiological function and protein expression.
abstract: Daurisoline (1) is a bis-benzylisoquinoline alkaloid isolated from the rhizomes of Menispermum dauricum. The antiarrhythmic effect of 1 has been demonstrated in different experimental animals. In previous studies, daurisoline (1) prolonged action potential duration (APD) in a normal use-dependent manner. However, the electrophysiological mechanisms for 1-induced prolongation of APD have not been documented. In the present study, the direct effect of 1 was investigated on the hERG current and the expression of mRNA and protein in human embryonic kidney 293 (HEK293) cells stably expressing the hERG channel. It was shown that 1 inhibits hERG current in a concentration- and voltage-dependent manner. In the presence of 10 μM 1, steady-state inactivation of V(1/2) was shifted negatively by 15.9 mV, and 1 accelerated the onset of inactivation. Blockade of hERG channels was dependent on channel opening. The expression and function of hERG were unchanged by 1 at 1 and 10 μM, while hERG expression and the hERG current were decreased significantly by 1 at 30 μM. These results indicate that 1, at concentrations below 30 μM, exerts a blocking effect on hERG, but does not affect the expression and function of the hERG channel. This may explain the relatively lower risk of long QT syndrome after long-term usage.
authors.affiliation: Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology , The Key Laboratory of Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, 430030, People's Republic of China.
authors.forename: Qiangni
authors.initials: Q
authors.lastname: Liu
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Mao
authors.forename: Fandian
authors.initials: F
authors.lastname: Zeng
authors.forename: Si
authors.initials: S
authors.lastname: Jin
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Yang
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D000889:Anti-Arrhythmia Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D044182:Benzylisoquinolines / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055724:Electrophysiological Phenomena; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D031603:Menispermum / Q000737:chemistry*; D015394:Molecular Structure; D012333:RNA, Messenger / Q000032:analysis; D027343:Rhizome / Q000737:chemistry
chemical_list: D000470:Alkaloids; D000889:Anti-Arrhythmia Agents; D044182:Benzylisoquinolines; D051638:Ether-A-Go-Go Potassium Channels; D012333:RNA, Messenger; C023968:daurisoline