Early and late sarcoplasmic reticulum changes in doxorubicin cardiomyopathy. An ultrastructural investigation with the zinc iodide-osmium tetroxide (ZIO) technique.

Abstract

The sequence of myocardial changes in the mouse induced by doxorubicin (Dx) treatment (10 mg/kg i.v.) has been investigated by electron microscopy with the help of the zinc iodide-osmium tetroxide (ZIO) technique. Accumulation of ZIO-reactive material, possibly oxidized glutathione and other disulfides, in the sarcoplasmic reticulum (S.R.) is among the earliest (1 h after Dx injection), more prominent and persistent findings (up to 100 days). It may have a pathogenic relationship with a number of functional and morphologic changes occurring in myocardial cells, including impairment of calcium transport and contractility, S.R. dilation up to extensive vacuolization, as well as inhibition of DNA, RNA and protein synthesis leading to atrophy and disruption of sarcomeres. The latter finding, first appearing in a few cells 4 to 7 days after Dx and progressively increasing in severity and extension during the next 3 months, may represent a key factor in the evolution of chronic cardiomyopathy to cardiac insufficiency. In most cells, only a minority of mitochondria showed obvious ultrastructural lesions, which were first observed 24 h after treatment and disappeared by the end of the first month, when no more mitochondrial damage was found outside degenerating cells. The myocardium of mice receiving multiple Dx injections (4 mg/Kg, 10 times, or 9 mg/Kg, 5 times) showed the same changes observed in animals treated with a single dose, though they were more severe and extensive.