Inhibitory effects of hesperetin on Nav1.5 channels stably expressed in HEK 293 cells and on the voltage-gated cardiac sodium current in human atrial myocytes.
OBJECTIVE
Voltage-gated sodium channels composed of a pore-forming α subunit and auxiliary β subunits are responsible for the upstroke of the action potential in cardiac myocytes. The pore-forming subunit of the cardiac sodium channel Nav1.5, which is encoded by SCN5A, is the main ion channel that conducts the voltage-gated cardiac sodium current (INa) in cardiac cells. The current study sought to investigate the inhibitory effects of hesperetin on human cardiac Nav1.5 channels stably expressed in human embryonic kidney 293 (HEK 293) cells and on the voltage-gated cardiac sodium current (INa) in human atrial myocytes.


METHODS
The effects of hesperetin on human cardiac Nav1.5 channels expressed in HEK 293 cells and on cardiac Na+currents in human atrial myocytes were examined through whole-cell patch-clamp techniques.


RESULTS
Nav1.5 currents were potently and reversibly suppressed in a concentration- and voltage-dependent manner by hesperetin, which exhibited an IC50of 62.99 μmol/L. Hesperetin significantly and negatively shifted the voltage-dependent activation and inactivation curves. Hesperetin also markedly decelerated Nav1.5 current inactivation and slowed the recovery from Nav1.5 channel inactivation. The hesperetin-dependent blockage of Nav1.5 currents was frequency-dependent. Hesperetin also potently and reversibly inhibited Na+current (INa) in human atrial myocytes, consistently with its effects on Nav1.5 currents in HEK 293 cells.


CONCLUSIONS
Hesperetin is a potent inhibitor of INain human atrial myocytes and Nav1.5 channels expressed in human embryonic kidney 293 cells. Hesperetin probably functions by blocking the open state and the inactivated state of these channels.
Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Huan
H
Wang
Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Hong-Fei
HF
Wang
Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Hao
H
Zhang
Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Chen
C
Wang
Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Yu-Fang
YF
Chen
Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Rong
R
Ma
Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Ji-Zhou
JZ
Xiang
Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Xin-Ling
XL
Du
Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Qiang
Q
Tang
D000368:Aged; D057809:HEK293 Cells; D006569:Hesperidin / Q000494:pharmacology*; D006801:Humans; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology*
D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D026941:Sodium Channel Blockers; D006569:Hesperidin; C013015:hesperetin
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