Adriamycin (ADR) is known to exert a severe negative inotropic effect on isolated myocardial preparations; a role for free radical generation has been hypothesized. Spin-trapping of free radicals has been extensively exploited in ESR studies, both in cell-free systems and in intact tissues. The interaction between spin-traps and free radicals should in principle stop the reaction cascade leading to cellular damage. Based on this hypothesis, the possible cardioprotective action of three spin-trapping agents, 5,5-dimethyl-l-pyrroline-N-oxide (DMPO), N-tert-butyl-alpha-phenylnitrone (PBN) and alpha-(4-pyridyl 1-oxide) N-tert-butylnitrone (POBN), was tested on isolated rat atria incubated in the presence of ADR; maximal non-cardiotoxic concentrations were used (50, 10 and 50 mM respectively) in order to achieve a maximal spin-trapping effect. A varying degree of protection was observed with the three compounds, directly correlated to their hydrophobicity, as assessed by chloroform/water partition coefficients. It is proposed that ADR-induced free radical generation is responsible for the acute cardiotoxic effects of the drug; this seems to be a site-specific mechanism restricted to one or more hydrophobic cellular compartment/s, since only lipophilic spin-trapping agents are able to prevent the development of the negative inotropic effect of ADR.