Huan Wang1, Hong-Fei Wang2, Hao Zhang2, Chen Wang1, Yu-Fang Chen1, Rong Ma1, Ji-Zhou Xiang1, Xin-Ling Du2, Qiang Tang1. 1. Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. 2. Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Abstract
AIM: 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 IC50 of 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. CONCLUSION: Hesperetin is a potent inhibitor of INa in 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.
AIM: 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 humanembryonic 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 IC50 of 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. CONCLUSION:Hesperetin is a potent inhibitor of INa in human atrial myocytes and Nav1.5 channels expressed in humanembryonic kidney 293 cells. Hesperetin probably functions by blocking the open state and the inactivated state of these channels.
Authors: Susann G Kaufmann; Ruth E Westenbroek; Alexander H Maass; Volkmar Lange; Andre Renner; Erhard Wischmeyer; Andreas Bonz; Jenny Muck; Georg Ertl; William A Catterall; Todd Scheuer; Sebastian K G Maier Journal: J Mol Cell Cardiol Date: 2013-05-20 Impact factor: 5.000