Virchows Archiv B

, Volume 54, Issue 1, pp 182–189 | Cite as

Effects of chronic administration of doxorubicin on myocardial alpha-adrenergic receptors, histamine, cyclic nucleotides, calcium, norepinephrine, calmodulin, and guanylate cyclase activity, and plasma catecholamines in rats

  • Timothy W. Robison
  • Shri N. Giri


The present study examined changes in the levels of plasma catecholamines and myocardial histamine, guanylate cyclase activity, cyclic nucleotides, calcium, calmodulin, and norepinephrine following chronic adminstration of doxorubicin (DXR). In addition, changes in myocardial alpha1-adrenergic receptor density and dissociation constant were measured. Rats received DXR (2 mg/kg) or vehicle weekly by the SC route for 2, 4, 8 and 13 weeks. Rats were sacrificed one week after their last dose. One group of rats treated for 13 weeks was sacrificed at 19 weeks, six weeks after the last dose. Heart histamine was unchanged at 3, 5, 9, and 19 weeks, yet at 14 weeks it was significantly elevated in DXR-treated rats over controls. Cardiac calcium, norepinephrine, and cyclic GMP levels were unchanged throughout the course of the study. Cardiac cAMP and calmodulin levels were unchanged at 3, 5, 9, and 14 weeks. At 19 weeks in DXR-treated rats, cAMP was depressed while calmodulin was elevated. Plasma catecholamines and myocardial guanylate cyclase activity examined at 14 weeks were unchanged. In contrast, alpha1 receptor density examined at 14 weeks in DXR-treated rats was significantly depressed while the dissociation constant was unchanged. Changes in cAMP and calmodulin are suggestive of a redistribution of calcium, although total levels of calcium were unchanged. The depression of cAMP indicates damage to the membrane bound enzyme, adenylate cyclase, and that the membrane interaction of doxorubicin appears to be an integral part of the biochemical mechanism of its toxicity.

Key words

Doxorubicin Catecholamines Alpha1-adrenergic receptors Calmodulin Cyclic nucleotides Calcium 


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Copyright information

© Springer-Verlag 1987

Authors and Affiliations

  • Timothy W. Robison
    • 1
  • Shri N. Giri
    • 1
  1. 1.Department of Veterinary Pharmacology and Toxicology, School of Veterinary MedicineUniversity of CaliforniaDavisUSA

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