Protection of rat heart from ischaemia-reperfusion injury by the 21-aminosteroid U-74389G.

In ischaemia-reperfusion syndromes lipid peroxidation appears an important factor contributing to tissue damage. The 21-aminosteroids (lazaroids) exhibit beneficial effects in various pathological conditions, especially in post-traumatic lesions of the central nervous system, where a peroxidative injury seems to be involved. The aim of our study was to ascertain if one of these compounds, U-74389G, plays a significant role in protecting heart muscle from ischaemia-reperfusion damage. Rat hearts used for heterotopic transplantation represented the experimental model in this investigation. Animals (Wistar rats weighing 200-250 g) were divided into five groups: controls, untreated and treated donors, untreated and treated recipients. Donors were anaesthetized and heparinized, and the heart was excised through a bilateral thoracotomy, arrested with St Thomas solution and stored in cold saline for 2 hours. For the recipient preparation, a modified Ono's technique was used, and heart reimplantation was performed with a termino-lateral aorto-aortic anasthomosis and a termino-lateral pulmonary-cava anasthomosis. After the anasthomoses were completed hearts were reperfused for 30 min; then hearts were excised and specimens were taken for biochemical and morphological studies. These were conducted on three groups of hearts: (A) hearts reimplanted and reperfused without treatment of the donor or of the recipient animal; (B) hearts subjected to the same procedure but in the presence of U-74389G treatment of donors and recipient rats; (C) control hearts rapidly excised from normal, non-operated animals. Electron microscopy studies showed, in hearts transplanted without treatment, the typical morphological aspects of lipoperoxidative injury: swollen mitochondria with disrupted cristae, damaged endothelial cells with the nucleous bulging into the lumen and a discontinued endothelial lining with diffuse oedema among the fibers. Lazaroid treatment attenuated most of these damages in hearts of group B. As for the biochemical findings, the hearts transplanted in the presence of U-74389G treatment had significantly higher ATP and creatine phosphate levels (P < 0.01) and lower malondialdehyde concentrations (P < 0.05) with respect to the hearts transplanted without treatment. Furthermore, serum creatine kinase activity was lower in treated than in untreated recipient animals (P < 0.05). Taken together, all these results indicate that U-74389G treatment is effective in protecting cardiac muscle from structural and functional ischaemia-reperfusion injuries, at least from those arising during a heart transplantation procedure.