A Molecular Biologic Approach to Cardiac Toxicology

  • Elwood O. Titus
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 161)


Molecular biology seeks to depict biological function in terms of discrete events, individually accessible to biochemical study. With the myocardial cell this approach has had some success. The affinity of receptors for a variety of drugs, the ionic basis for signal transmission across the sarcolemmal membrane, and the enzymatic components of the various membranes that control internal calcium, have been studied and provide a rationale for at least some of the reversible, pharmacologically induced dysfunctions that represent the side effects of conventional drugs on this cell. This symposium, however, deals largely with chemical agents which initiate sequences of incompletely understood events that lead ultimately to irreversible tissue damage and cell death. Among these effects, the myocardial necrosis produced by suprapharmacological concentrations of isoproterenol has been of special interest because its production may have some elements in common with infarction or ischemic damage and because it induces resistance to further chemical damage.


Xanthine Oxidase Myocardial Necrosis Free Radical Damage Spin Trapping Sarcolemmal Membrane 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    BALAZS, T., OHTAKE, S. & NOBLE, J.F. The development of resistance to the ischemic cardiopathic effect of isoproterenol. Toxicology and Applied Pharmacology21, 200–213 (1972).PubMedCrossRefGoogle Scholar
  2. 2.
    BLOOM, S. Reversible and irreversible injury; Calcium as a major determinant. In Cardiac Toxicology, Vol. 1, T. Balazs, Ed., pp. 179–201. Boca Raton: CRC Press (1981).Google Scholar
  3. 3.
    BLOOM, S. & CANCILLA, P. Myocytolysis and mitochondrial calcification in rat myocardium after low doses of isoproterenol. American Journal of Pathology54, 373–391 (1969).PubMedGoogle Scholar
  4. 4.
    BLOOM, S. & DAVIS, D. Calcium as mediator of isoproterenol-induced myocardial necrosis. American Journal of Pathology69, 459–470 (1972).PubMedGoogle Scholar
  5. 5.
    BRISTOW, M.R., MASON, J.W., BILLINGHAM, M.E. & DANIELS, J.R. Doxorubicin cardiomyopathy; Evaluation by phonocardiography, endomyocardial biopsy, and cardiac catheterization. Annals of Internal Medicine88, 168–175 (1978).PubMedGoogle Scholar
  6. 6.
    BUETTNER, G.R. & OBERLEY, L.W. Considerations in the spin trapping of superoxide and hydroxyl radical in aqueous systems using 5,5-dimethyl-l-pyrroline-1-oxide. Biochemical and Biophysical Research Communications83, 69–74 (1978).PubMedCrossRefGoogle Scholar
  7. 7.
    DEMOPOULOS, H.B., FLAMM, E.S., PIETRONIGRO, D.D. & SELIGMAN, M.L. The free radical pathology and the microcirculation in the major central nervous system disorders. Acta Physiologica Scandinavica Supplementum492, 91–119 (1980).PubMedGoogle Scholar
  8. 8.
    DOROSHOW, J.H., LOCKER, G.Y. & MYERS, G.E. Enzymatic defenses of the mouse heart against reactive oxygen metabolites: Alterations produced by doxorubicin. Journal of Clinical Investigation65, 128–135 (1980).PubMedCrossRefGoogle Scholar
  9. 9.
    EVANS, C.A. Spin trapping. Aldrichimica Acta12, 23–29 (1979).Google Scholar
  10. 10.
    FLECKENSTEIN, A., JANKE, J., DORING, H. & LEDER, O. Myocardial fiber necrosis due to intracellular calcium overload — a new principle in cardiac pathophysiology. Recent Advances in Studies on Cardiac Structure and Metabolism4, 563–580 (1974).PubMedGoogle Scholar
  11. 11.
    GOODMAN, J. & HOCHSTEIN, P. Generation of free radicals and lipid peroxidation by redox cycling of adriamycin and daunomycin. Biochemical and Biophysical Research Communications77, 797–803 (1977).PubMedCrossRefGoogle Scholar
  12. 12.
    HERMAN, E. Cardiotoxicity of anti-neoplastic drugs. In Cardiac Toxicology, Vol. 2, T. Balazs, Ed., pp. 165–189. Boca Raton: CRC Press (1981).Google Scholar
  13. 13.
    ITO, K., KARAKI, H. & URAKAWA, N.. Effects of palytoxin on mechanical and electrical activities of guinea pig papillary muscle. Japanese Journal of Pharmacology29, 467–476 (1979).PubMedCrossRefGoogle Scholar
  14. 14.
    JANZEN, E.G. A critical review of spin trapping in biological systems. In Free Radicals in Biology, Vol. 4, W.A. Pryor, Ed., pp. 115–154. New York: Academic Press (1980).Google Scholar
  15. 15.
    JANZEN, E.G., WANG, Y.Y. & SHETTY, R.V. Spin trapping with a-pyridyl-1-oxide N-tert-butyl nitrones in aqueous solution. A unique electron spin resonance spectrum for the hydroxyl radical adduct. Journal of the American Chemical Society100, 2923–2925 (1978).CrossRefGoogle Scholar
  16. 16.
    KAPPUS, H. & SIES, H. Toxic drug effects associated with oxygen metabolism: Redox cycling and lipid peroxidation. Experientia37, 1233–1241 (1981).PubMedCrossRefGoogle Scholar
  17. 17.
    KLUGMANN, S., BARTOLI KLÜGMANN, F., DECORTI, G., GORI, D., SYLVESTRI, F. & CAMERINI, F. Adriamycin experimental cardiomyopathy in Swiss mice. Different effects of two calcium antagonistic drugs on ADM-induced cardiomyopathy. Pharmacological Research Communications13, 769–776 (1981).PubMedCrossRefGoogle Scholar
  18. 18.
    LAI, E.K., McKAY. P.B., NOGUCHI, T. & FONG, K. In vivo spin trapping of trichloromethyl radicals formed from CCl4. Biochemical Pharmacology28, 2231–2235 (1979).PubMedCrossRefGoogle Scholar
  19. 19.
    LEHR, D. Studies on the cardiotoxicity of alpha and beta adrenergic amines. In Cardiac Toxicology, Vol. 2, T. Balazs, Ed., pp. 75–113. Boca Raton: CRC Press (1981).Google Scholar
  20. 20.
    LEHR, D., CHAU, R. & IRENE, S. Possible role of magnesium loss in the pathogenesis of myocardial fiber necrosis. Recent Advances in Studies on Cardiac Structure and Metabolism 6, 95–109 (1975).PubMedGoogle Scholar
  21. 21.
    LUCCHESI, B., BURNREISTER, W., LOMAS, T. & ABRAMS, G. Ischemic changes in the canine heart as affected by the dimethyl quaternary analog of propranolol, UM 272. Journal of Pharmacology and Experimental Therapeutics199, 310–328 (1976).PubMedGoogle Scholar
  22. 22.
    McCORD, J.M. Superoxide, superoxide dismutase and oxygen toxicity. In Reviews in Biochemical Toxicology, Vol. 1., E. Hodgson, J.R. Bend & R.M. Philpot, Eds., pp. 109–124. New York: Elsevier/North Holland (1979).Google Scholar
  23. 23.
    MOORE, R.E. & BARTOLINI, G. Structure of palytoxin. Journal of the American Chemical Society103, 2491–2494 (1981).CrossRefGoogle Scholar
  24. 24.
    OLSON, H.M., YOUNG, D.M., PRIEUR, D.J., LeROY, A.F. & REAGAN, R.L. Electrolyte and morphologic alterations of myocardium in adriamycin-treated rabbits. American Journal of Pathology 77, 439–454 (1974).PubMedGoogle Scholar
  25. 25.
    OLSON, R.D., BOERTH, R.C., GERBER, J.G. & NILES, A.S. Mechanism of adriamycin eardiotoxicity: Evidence for oxidative stress. Life Sciences29, 1393–1401 (1981).PubMedCrossRefGoogle Scholar
  26. 26.
    PARKS, D.A., BÜLKLEY, G.B., GRANGER, D.N., HAMILTON, S.R. & McCORD, J.M. Ischemic injury in the cat small intestine: Role of superoxide radicals. Gastroenterology 82, 9–15 (1982).PubMedGoogle Scholar
  27. 27.
    REIMER, K.A., RASMUSSEN, M.M. & JENNINGS, R.B. On the nature of protection by propranolol against myocardial necrosis after temporary coronary occlusion in dogs. American Journal of Cardiology37, 520–527 (1976).PubMedCrossRefGoogle Scholar
  28. 28.
    ROSEN, G.M. & RAUCKMAN, E.J. Spin trapping of free radicals during hepatic microsomal lipid peroxidation. Proceedings of the National Academy of Sciences, USA78, 7346–7349 (1981).CrossRefGoogle Scholar
  29. 29.
    ROSSI, C.S. & LEHNINGER, A.L. Stoichiometric relationships between accumulation of ions by mitochondria and the energy-coupling sites in the respiratory chain. Biochemische Zeitschrift338, 698–713 (1963).PubMedGoogle Scholar
  30. 30.
    ROY, R.S. & McCORD, J.M. Ischemic-induced conversion of xanthine dehydrogenase to xanthine oxidase. Federation Proceedings 41, 767 (1982).Google Scholar
  31. 31.
    SELYE, H. The Chemical Prevention of Necrosis. New York: Ronald Press (1958).Google Scholar
  32. 32.
    TSIEN, R.Y. New calcium indicators and buffers with high selectivity against magnesium and protons. Design, synthesis, and properties of prototype structures. Biochemistry 19, 2396–2404 (1980).PubMedCrossRefGoogle Scholar
  33. 33.
    TSIEN, R.Y. A non-disruptive technique for loading calcium buffers and indicators into cells. Nature290, 527 (1981).PubMedCrossRefGoogle Scholar
  34. 34.
    VAN VLEET, J.F., GREENWOOD, L., FERRANS, V.J. & REBAR, A.H. Effect of selenium-vitamin E on adriamycin-induced cardiomyopathy in rabbits. American Journal of Veterinary Research 39, 997–1010 (1978).PubMedGoogle Scholar
  35. 35.
    VICK, J.A. & WILES, J.S. The mechanism of action and treatment of palytoxin poisoning. Toxicology and Applied Pharmacology 34, 214–223 (1975).PubMedCrossRefGoogle Scholar
  36. 36.
    WAUD, W.R. & RAJAGOPALAN, K.V. The mechanism of conversion of rat liver xanthine dehydrogenase from an NAD+-dependent form (type D) to an 02-dependent form (type 0). Archives of Biochemistry and Biophysics172, 365–379 (1976).PubMedCrossRefGoogle Scholar
  37. 37.
    WEXLER, B.C. & McMURTRY, J.P. Allopurinol amelioration of the pathophysiology of acute myocardial infarction in rats. Atherosclerosis39, 71–87 (1981).PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1983

Authors and Affiliations

  • Elwood O. Titus
    • 1
  1. 1.Division of Drug BiologyBureau of Drugs, Food and Drug AdministrationUSA

Personalised recommendations