Mechanisms of probucol protection against development of adriamycin-induced cardiomyopathy

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Siveski-Iliskovic, Natasa
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Our laboratory has demonstrated protection against adriamycin-cardiomyopathy by probucol. Probucol is: (I) a lipid lowering drug; (II) a strong antioxidant; and (III) shown by us to increase superoxide dismutase (SOD) and glutathione peroxidase (GSHPx) activities. The objectives of this thesis research was to define further the mechanism for the protective effect of probucol and to test the antitumor efficacy of adriamycin in the proposed adjunct therapy. We induced adriamycin cardiomyopathy and heart failure in rats by a procedure established in our laboratory. Beneficial effects of lipid-lowering as well as of an increase in myocardial antioxidants were analysed by comparing effects of probucol with another lipid-lowering drug (lovastatin) as well as another antioxidant (trolox). We monitored hemodynamic function; cardiomyopathic changes; myocardial antioxidant enzyme activities, glutathione (reduced (GSH) and oxidized (GSSG)) and lipid peroxidation. Plasma lipids, plasma albumin levels, serum free fatty acids as well as cardiac lipids were also analysed. Whether probucol modifies antitumor property of adriamycin was answered by comparing the effects of adjunct therapy with that of adriamycin alone in tumor bearing mice. Male Sprague-Dawley rats weighing 250 $\pm$ 25 g were divided into different groups: CONT (control), ADR (adriamycin), PROB (probucol), PRO + ADR (probucol + adriamycin), LOV (lovastatin), LOV + ADR (lovastatin + adriamycin), TRO (trolox), TRO + ADR (trolox + adriamycin). Adriamycin was administered in a total cumulative dose of 15 mg/kg body weight to ADR, PROB + ADR, LOV + ADR and TRO + ADR groups. Probucol (cumulative dose 120 mg/kg body weight), lovastatin (48 mg/kg cumulative dose) and trolox (48 mg/kg, cumulative dose) were also administered two weeks prior to treatment with adriamycin and two weeks alternating with adriamycin. After 3 weeks of post-treatment period, rats in the ADR group showed reduced weight gain, and 45% mortality and development of congestive heart failure. In the PROB + ADR group, probucol treatment completely prevented development of congestive heart failure and normalized all parameters that were pathologically changed due to adriamycin administration. In the LOV + ADR group, lovastatin significantly attenuated but did not completely prevent cardiomyopathic changes due to adriamycin. In the TRO + ADR group, trolox treatment significantly improved but did not completely prevent development of adriamycin-induced cardiomyopathy. Experiments, done on tumor inoculated mice, showed comparable decrease in tumor size in both ADR and PROB + ADR groups of mice. Our data show that ADR cardiomyopathy as well as heart failure are associated with an antioxidant deficit, lipid peroxidation, increase in myocardial and plasma lipidsas well as increase in FFA/albumin ratio. Improved cardiac function and zero mortality with probucol in ADR treated animals may be related to the maintenance of the antioxidant status, improved redox ratio, and prevention of lipid peroxidation in the heart along with the normalization of the myocardial and plasma lipids as well as FFA/albumin ratio. Since lovastatin or trolox either improved lipid profile or prevented lipid peroxidation but never both simultaneously, there was only a partial improvement in cardiac function with these drugs. Probucol, with its unique combination of lipid lowering properties, innate antioxidant activity (in the lipid phase), and promotion of endogenous antioxidants appears to have an optimal combination of characteristics. (Abstract shortened by UMI.)