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Thrombin facilitation of voltage-gated sodium channel activation in human cardiomyocytes: implications for ischemic
Caroline Pinet1, Bruno Le Grand, Gareth W John
1Centre Nationale de la Recherche Scientifique, Unité Mixte de Recherche 8078, Hôpital Marie Lannelongue, Le Plessis Robinson, France.
Insights
Thrombin enhances cardiac sodium channel activity, increasing sodium current and potentially causing ischemic injury. This study investigates thrombin
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Ion Channel Function
Background:
- Thrombin's role in ischemic injury and arrhythmias is unclear.
- Voltage-gated sodium channels (VGSCs) were not previously implicated.
- This study explores thrombin's effects on VGSCs in human cardiomyocytes.
Purpose of the Study:
- To investigate the effects of thrombin on voltage-gated sodium channel (VGSC) function.
- To elucidate the mechanisms by which thrombin influences cardiomyocyte electrophysiology.
Main Methods:
- Whole-cell patch-clamp recordings of sodium current (I(Na)) in human isolated cardiomyocytes.
- Assessed thrombin's dose-dependent effects on I(Na) amplitude and kinetics.
- Investigated the impact of thrombin on resting membrane potential and window current.
Main Results:
- Thrombin significantly increased peak I(Na) amplitude in an activity-dependent manner (EC50 of 91+/-16 U/mL).
- Thrombin shifted I(Na) activation to hyperpolarized potentials, increasing window current without altering inactivation.
- Thrombin (32 U/mL) depolarized the resting membrane potential by 10 mV.
Conclusions:
- Facilitation of VGSC activation by thrombin increases window current.
- This mechanism likely contributes to thrombin-induced ischemic sodium loading and cardiac injury.
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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