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The aim of this study was to investigate whether the renoprotective effect of angiotensin–converting enzyme inhibitors (ACEIs) following 5/6 renal mass reduction is due in part to the potentiation of kinins. Three groups of rats with 5/6 renal mass reduction were studied during the 14 weeks following surgery. One group received no therapy (control); the second group was treated from the beginning with the ACEI ramipril (1 mg/kg/day) added to the drinking water, and the last group received ramipril plus a β₂–bradykinin antagonist, HOE 140 (500 μg/kg/day) via osmotic minipumps. Plasma creatinine did not change in any group during the study. Urinary protein excretion rose in the controls from 9.18±1.6 to 45.0±5.6 mg/24 h at the end of the study. In ramipril group proteinuria was prevented (initial 7.5±1.0 and final 8.6±0.8 mg/24h). The effect of ramipril was abolished by HOE 140 (initial 11.6±2.0 and final 38.9±11 mg/ 24h). The systolic blood pressure of the controls increased from 106±2 to 144±5mmHg at the 14th week. Ramipril abolished the increase in systolic blood pressure. The effect of ramipril was reverted by HOE 140 (initial 108±2 and final 140±9 mmHg). Control rats had more severe histopathologic changes. Those animals receiving ramipril + HOE 140 displayed less severe glomerular changes, while rats treated only with ramipril had mild alterations. Thus the glomerular injury score was 2.11±0.32 for controls, 1.53±0.52 for rats treated with ramipril + HOE 140, and 0.06±0.04 for rats treated only with ramipril. The glomerular area was 20,886±1,410, 19,693±2,200 and 14,352±3,200 μm², respectively, for the 3 groups. These results suggest that the protective effect of ACEIs in the development of chronic renal failure is partially mediated by kinins.

Fenofibrate, the hypolipidemic drug and peroxisome proliferator, was given to mice (0.23% w/w in the diet) during 1-3 weeks and H2O2 and TBARS steady state concentrations, liver chemiluminescence and antioxidant levels were measured. Administration of fenofibrate during 2 weeks induced an increase of 89% in H2O2 steady state concentration. Spontaneous chemiluminescence was decreased by 57% during fenofibrate treatment, while no significant effect was observed on TBARS concentration. Hydroperoxide-initiated chemiluminescence was decreased by 56% after 15 days of fenofibrate treatment, probably due to an increase in endogenous antioxidant levels. Total and oxidized glutathione increased gradually after fenofibrate administration, obtaining maximal increases of 67% and 58% respectively, after 22 days of treatment. An increase of 55% was found in ubiquinol levels in treated mice, as compared with the controls. alpha-tocopherol content was decreased by 51% in the liver of fenofibrate-treated mice. According to our findings, the high rate of H2O2 production associated with peroxisome proliferation, would not lead to an increase in lipid peroxidation. This can be explained by the presence of high levels of ubiquinols, which act as an antioxidant. The increased production of H2O2, would lead to DNA damage directly, and not through lipid peroxidation processes.

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While results with inhibitors of thiol proteases have led to the suggestion that the progressive increase with age of lipofuscin in post-mitotic and some stable cells may be due to an age-related decline in the activity of these enzymes (Ivy et al., 1989), no direct evidence has been yet presented to support this hypothesis. In this study Wistar female rats were killed at age of 5, 14, and 24 months and the amounts of lipofuscin were histologically quantitated in neurons of the left cerebral parietal cortex and in cardiac myocytes of left ventricle. The sites of cathepsin B activity histochemically detected were quantitated in sections from left cerebral parietal cortex and left ventricle, and the activity of this enzyme was also measured biochemically in brain and heart homogenates. In line with previous findings, the amounts of lipofuscin in neurons and cardiac myocytes increased linearly during development and aging (from 5 to 14 and from 14 to 24 mo.). The sites of cathepsin B activity histochemically detected in sections from cerebral cortex significantly increased from 5 to 14 mo., but remained unchanged from 14 to 24 mo, while in sections from the left cardiac ventricle these sites of activity remained unchanged during development, and significantly increased during aging. On the other hand the biochemically determined activities of cathepsin B in brain and heart homogenates remained unchanged from 5 to 14 mo., but significantly decreased from 14 to 24 mo. These results suggest that the increase in lipofuscin with age may not be due to an age-wise decline in cathepsin B activity.