Comparison of the severity of the chronic cardiotoxicity produced by doxorubicin in normotensive and hypertensive rats

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Abstract

A comparison was made of the severity of chronic doxorubicin cardiotoxicity in adult male spontaneously hypertensive rats (SHR) and in genetically related normotensive Wistar-Kyoto rats (WKY). Groups of SHR and WKY were given 12 weekly iv injections of doxorubicin at 0.25, 0.5, or 1.0 mg/kg. When the study was concluded, mean arterial pressure was 127 to 161 nm Hg in doxorubicin-treated SHR compared with 74 to 87 mm Hg in similarly treated WKY. Lesions, consisting mainly of cytoplasmic vacuolization and myofibrillar loss, were noted in the hearts from both types of rats given the 1.0-mg/kg dose and were considerably more severe in SHR than in WKY (average scores 3.8 and 2.0). Renal lesions (glomerular vacuolization and dilatation of tubules with accumulations of proteinaceous material) were of comparable severity in both types of rats at the 9- and 12-mg/kg cumulative doses; however, they were more severe in SHR at the 6-mg/kg cumulative dose. Moderate cardiac alterations were present in all SHR (average score 1.6) given 0.5 mg doxorubicin/kg; at the same dose, lesions were minimal in two and absent in three WKY. In a second study, groups of rats were killed 1 week after 3, 6, 9, or 12 weekly iv injections of doxorubicin (1.0 mg/kg). Myocardial lesions were noted initially in SHR after six doses and in WKY after nine doses. Three of five SHR were dead by the 12th dose. These results indicate that spontaneously hypertensive rats are much more sensitive than normotensive rats to the cardiotoxic effects of doxorubicin.

References (28)

  • Z. Ben-Zvi et al.

    Drug disposition in spontaneously hypertensive rats

    Pharmacol. Res. Commun.

    (1980)
  • J.R. Martin et al.

    Differential sensitivity of spontaneously hypertensive rats to the hypothermic effect of dopaminergic drugs

    Life Sci.

    (1980)
  • K.J. Widder et al.

    Experimental methods in cancer therapeutics

    J. Pharm. Sci.

    (1982)
  • T. Bertani et al.

    Adriamycin-induced nephrotic syndrome in rats

    Lab. Invest.

    (1982)
  • R.H. Blum et al.

    Adriamycin: A new anticancer drug with significant clinical activity

    Ann. Intern. Med.

    (1974)
  • J.F. Burke et al.

    Doxorubicin hydrochloride-associated renal failure

    Arch. Intern. Med.

    (1977)
  • R.T. Chlebowski et al.

    Adriamycin given as a weekly schedule without a loading course: Clinically effective with reduced incidence of cardiotoxicity

    Cancer Treat. Rep.

    (1980)
  • E.P. Cortes et al.

    Adriamycin (NSC123127) cardiotoxicity: A clinicopathologic correlation

    Cancer Chemother. Rep.

    (1975)
  • J.H. Doroshow et al.

    Prevention of doxorubicin cardiac toxicity in the mouse by N-acetylcysteine

    J. Clin. Invest.

    (1981)
  • S.M. Factor et al.

    Hypertensive diabetic cardiomyopathy in the rat: Ultrastructural features

    Virchows Arch. Pathol. Anat.

    (1983)
  • E.H. Herman et al.

    Pretreatment with ICRF-187 markedly reduces chronic doxorubicin cardiotoxicity in beagle dogs

    Cancer Res.

    (1981)
  • E.H. Herman et al.

    Influence of vitamin E and ICRF-187 on chronic doxorubicin cardiotoxicity in miniature swine

    Lab. Invest.

    (1983)
  • S.T. Hu et al.

    Inhibition of cardiotoxic, nephrotoxic and neurotoxic effects of doxorubicin by ICRF-159

    Pharmacology

    (1983)
  • E.A. Lefrak et al.

    Clinicopathologic analysis of Adriamycin cardiotoxicity

    Cancer

    (1973)
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