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 (I_Na) was recorded by the whole-cell patch-clamp method. Thrombin increased peak I_Na 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 I_Na was abolished by tetrodotoxin (50 µmol/L). Thrombin effects on I_Na were reversible and repeatable, and 100 U/mL doubled peak I_Na amplitude. Thrombin (32 U/mL) shifted I_Na 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.