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  • Title: Thrombin facilitation of voltage-gated sodium channel activation in human cardiomyocytes: implications for ischemic sodium loading.
    Author: Pinet C, Le Grand B, John GW, Coulombe A.
    Journal: Circulation; 2002 Oct 15; 106(16):2098-103. PubMed ID: 12379580.
    Abstract:
    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 micromol/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 micromol/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.
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