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The cardiotoxicity of anthracycline antibiotic anti-tumor agents is well-described but the molecular basis of the cardiotoxicity is not understood. We examined the effect of doxorubicin (Adriamycin) on the activity of guanylate cyclase (E.C. 4.6.1.2), the enzyme catalyzing the production of guanosine 3′,5′-monophosphate, from rat heart, liver, lung, kidney, and spleen. Doxorubicin produced a decrease in cardiac guanylate cyclase activity over the concentration range 0.4 to 2 m m but was without effect, or slightly stimulated, guanylate cyclase from the other tissues. Daunorubicin (Daunomycin), a related, cardiotoxic anthracycline antibiotic also decreased cardiac guanylate cyclase activity over the concentration range 0.8 to 4 m m . Other antibiotic anti-tumor agents which are not cardiotoxic, including streptonigrin, porfiromycin, and mitomycin C did not decrease cardiac guanylate cyclase activity. Doxorubicin, 1 m m and 2 m m , and daunorubicin, 4 m m decreased cardiac guanylate cyclase approximately 50% in experiments utilizing guanylate cyclase prepared from human heart. The data suggests that some aspects of anthracycline cardiotoxicity may be related to altered cardiac guanylate cyclase activity.