Thrombin Facilitation of Voltage-Gated Sodium Channel Activation in Human Cardiomyocytes
Implications for Ischemic Sodium Loading
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Background— Thrombin plays a role in mediating ischemic injury and cardiac arrhythmias, but the mechanisms involved are poorly understood. Because voltage-gated sodium channels (VGSCs) have not previously been considered, putative effects of thrombin on VGSC function were investigated in human isolated cardiomyocytes.
Methods and Results— Sodium current (INa) was recorded by the whole-cell patch-clamp method. Thrombin increased peak INa amplitude in an activity-dependent manner, from 1 to 100 U/mL, with an apparent EC50 of 91±16 U/mL. When tested at 32 U/mL, thrombin-increased INa was abolished by tetrodotoxin (50 μmol/L). Thrombin effects on INa were reversible and repeatable, and 100 U/mL doubled peak INa amplitude. Thrombin (32 U/mL) shifted INa activation to hyperpolarized potentials without affecting steady-state inactivation, producing unusually large increases in window current. Hirudin (320 U/mL) or haloenol lactone suicide substrate (10 μmol/L) failed to significantly affect these effects of thrombin. In current-clamped cardiomyocytes, thrombin (32 U/mL) depolarized resting membrane potential by 10 mV.
Conclusions— Facilitation of VGSC activation causing large increases in window current is a major mechanism by which thrombin may promote ischemic sodium loading and injury.
Received May 29, 2002; revision received July 29, 2002; accepted August 6, 2002.