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(Circulation. 2002;106:2098.)
© 2002 American Heart Association, Inc.

Clinical Investigation and Reports

Thrombin Facilitation of Voltage-Gated Sodium Channel Activation in Human Cardiomyocytes

Implications for Ischemic Sodium Loading

From the Centre Nationale de la Recherche Scientifique, Unité Mixte de Recherche 8078 (C.P., A.C.), Hôpital Marie Lannelongue, Le Plessis Robinson, and the Division of Cardiovascular Diseases (B.L.G., G.W.J.), Centre de Recherche Pierre Fabre, Castres, France.

Correspondence to Dr Alain Coulombe, Hôpital Marie Lannelongue, 133 Ave de la Résistance, F92350 Le Plessis Robinson. E-mail alain.coulombe{at}ccml.u-psud.fr

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.

Key Words: ion channels • sodium • thrombosis • ischemia • myocytes

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