Prior studies have suggested that physostigmine may be useful in reversing QRS prolongation due to amitriptyline toxicity. To investigate this question, we devised a pharmacologic model in rabbits utilizing an initial intravenous bolus of amitriptyline (4-6 mg) followed by a constant amitriptyline infusion (0.2-0.4 mg/min) empirically titered to maintain the QRS at 50% or more of control value for at least 5 min. Intravenous physostigmine (2 mg) sufficient to produce muscle fasciculations and significant (P less than 0.01) slowing of sinus rate was then administered to six animals. No significant change in QRS duration was noted at 1, 3, and 5 min intervals following physostigmine. Although no immediate antidotal effect of physostigmine on amitriptyline-induced QRS prolongation could be demonstrated, these results do not exclude a possible interaction between the membrane effects of the tricyclic antidepressants (and related agents) and the vagal branch of the autonomic nervous system.