The effect of amitriptyline that leads to ventricular tachycardia was evaluated by the repetitive extrasystole threshold (RET) technique in 18 dogs. The RET was 28.8 +/- 7.9 mamp before and 8.2 +/- 5.3 mamp after amitriptyline, p less than 0.001. Physostigmine, propranolol, sodium bicarbonate, and left stellate ganglionectomy reversed the effect of amitriptyline on RET. We conclude that amitriptyline overdose predisposes to sudden death by lowering the ventricular fibrillation threshold. This cardiotoxic effect is mediated partly through the central nervous system and can be inhibited by increased plasma binding (bicarbonate), cholinergic stimulation (physostigmine), beta adrenergic blockade (propranolol), and sympathetic denervation (left stellate ganglionectomy).