Abstract
Tricyclic antidepressants are known to induce cardiac arrhythmias at therapeutic or supratherapeutic doses. The tricyclic antidepressant, amitriptyline, is reported to induce ST segment elevation in the right precordial electrocardiogram (ECG) leads, thus unmasking Brugada syndrome (BrS). The mechanism by which antidepressants induce the BrS phenotype and associated sudden death is not well established. Action potentials (AP) were simultaneously recorded from epicardial and endocardial sites of isolated coronary-perfused canine right ventricular wedge preparations, together with a transmural pseudo-ECG. Amitriptyline alone (0.2 μM-1 mM) failed to induce a BrS phenotype. NS5806 (8 μM), a transient outward potassium channel current (I(to) ) agonist, was used to produce an outward shift of current mimicking a genetic predisposition to BrS. In the presence of NS5806, a therapeutic concentration of amitriptyline (0.2 μM) accentuated the epicardial AP notch leading to ST-segment elevation of the ECG. All-or-none repolarization at some epicardial sites but not others gave rise to phase-2-reentry and polymorphic ventricular tachycardia (VT) in 6 of 9 preparations. Isoproterenol (100 nM) or quinidine (10 μM) reversed the effects of amitriptyline aborting phase 2 reentry and VT (4/4). Using voltage-clamp techniques applied to isolated canine ventricular myocytes, 0.2 μM amitriptyline was shown to produce use-dependent inhibition of sodium channel current (I(Na) ), without significantly affecting I(to) (n = 5). Our data suggest that amitriptyline-induced inhibition of I(Na) unmasks the Brugada ECG phenotype and facilitates development of an arrhythmogenic substrate only in the setting of a genetic predisposition by creating repolarization heterogeneities that give rise to phase 2 reentry and VT.
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