Cardiovascular toxicity induced by dimetacrine (DMC), an antidepressant, was investigated in isolated guinea pig atria and anesthetized dogs, and compared with those of imipramine (IMP) and amitriptyline (AMT) which have been widely used as antidepressants. In the electrically driven guinea pig left atria, these three agents depressed the atrial contraction; a statistically significant differences from non-treated control atria was observed in IMP and AMT, 3 times 10- minus 6M, and DMC, 10-5 minus M. The following order of potency was obtained; AMT greater than IMP greater than DMC. In the anesthetized dogs treated with the increasing doses of each agent, hypotensive response were observed in the doses more than 1 mg/kg i.v.; the order of potency was as follows, AMT greater than IMP greater than DMC. A pronounced tachycardia was induced by IMP and AMT, 0.1-3 mg/kg i.v., and DMC, 1-3 mg/kg i.v., and the maximum response was observed in the doses of 1, 1 and 3 mg/kg i.v., respectively. When infused at the rate of 1 mg/kg/min i.v., the agents elicited hyperpnoea, tachycardia (except DMC) and hypotension, followed by respiratory arrest and cardiac arrest. Various changes in the ECG, including extrasystoles and supraventricular or ventricular tachycardia were also observed 10 to 15 min after the onset of infusion of AMT and IMP. However, DMC caused no visible modification in the ECG. The doses of AMT, IMP and DMC required to produce cardiac arrest were 25.4 plus or minus 1.2 (S.E.M.), 27.5 plus or minus 3.8 and 64.0 plus or minus 2.2 mg/kg i.v., respectively. The present study confirmed that fewer cardiovascular complications are caused by clinical use of DMC as compared to other tricyclic antidepressants such as IMP or AMT.