Blockade of Cardiac Sodium Channels by Amitriptyline and Diphenylhydantoin: Evidence for Two Use-Dependent Binding Sites

• Published in: Circulation research 1991-09, Vol.69 (3), p.677-696
• Main Authors: Barber, Michael J, Starmer, C Frank, Grant, Augustus O
• Format: Article
• Language: English
• Subjects: amitriptyline; Amitriptyline - metabolism; Amitriptyline - pharmacology; Animals; Binding Sites; Binding, Competitive; Biological and medical sciences; cardiac muscle; channels; diphenylhydantoin; Drug toxicity and drugs side effects treatment; Heart - drug effects; In Vitro Techniques; inactivation; Lidocaine - metabolism; Lidocaine - pharmacology; Medical sciences; Myocardium - cytology; Myocardium - metabolism; Pharmacology. Drug treatments; Phenytoin - metabolism; Phenytoin - pharmacology; Rabbits; sodium; Sodium - metabolism; Sodium - physiology; Sodium Channels - drug effects; Sodium Channels - metabolism; Toxicity: cardiovascular system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.res.69.3.677

Cardiac toxicity is a frequent manifestation in amitriptyline overdose and is felt to be due, in part, to sodium channel blockade by the drug. Another agent with sodium channel blocking properties, diphenylhydantoin, has been used clinically to reverse cardiac conduction abnormalities induced by amitriptyline. This reversal of toxicity is believed to occur secondary to competition for the sodium channel binding site. We evaluated individually and in combination the effects of amitriptyline (0.4 μM) and diphenylhydantoin (10–80 μM) on the sodium current in isolated rabbit atrial and ventricular myocytes at 17°C. Using the whole-cell variant of the patch-clamp technique, we found that both amitriptyline and diphenylhydantoin reduced the sodium current in a use-dependent fashion. The time constant of recovery (τr) from block by amitriptyline at −130 mV was very slow (13.6±3.2 seconds), whereas τr during diphenylhydantoin exposure was fast (0.71±0.21 seconds, p