The effect of neocuproine on cardiac injury was studied using retrogradely perfused isolated rat hearts in two experimental systems. In the first system, where hydrogen peroxide-induced damage was studied, neocuproine at the range of 40-175 microM provided protection at the level of 70-85%, as demonstrated by the reduced loss in the peak systolic pressure (P), in +dP/dt and in -dP/dt. In the second system, where ischemia/reperfusion-induced arrhythmias were studied, neocuproine (42 microM) provided a marked protection against cardiac injury as demonstrated by the lowering of the incidence in irreversible ventricular fibrillation, by decreasing the duration of ventricular fibrillation and by the concomitant increase of the duration of normal sinus rhythm, and by improving the post-ischemic recovery of P, +dP/dt and -dP/dt. Free radicals have already been implicated as causative agents in cardiac injury resulting from either hydrogen peroxide or ischemia followed by reperfusion. Additionally, iron and copper have already been shown to drastically exacerbate the injurious effects of free radicals. Thus, the results reported here with neocuproine, a highly effective chelator for both iron and copper, as well as with adventitious copper and with the combination of neocuproine and copper, are in accord with the mediatory role of transition metals in enhancing the deleterious effects induced by free radicals.