Influence of Losartan and Enalapril on Urinary 8-isoprostane Excretion in
Experimental Nephrotic Syndrome
Tesař V.,
1
Zima T., Jirsa M., jr.,
1
Crkovská J.,
1
Štípek S.,
2
Vernerová Z., Šeráková M.
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Abstract:
Background. Increased permeability of glomerular capillary wall in adriamycin nephropathy may be mediated
by increased generation of free radicals and possibly also by the non-enzymatic production of isoprostanes induced
by oxidative stress. ACE inhibitors may reduce proteinuria, possibly due to the decrease of intraglomerular pressure
and increased permselectivity of the glomerular capillary wall. These effects may be partly mediated by the inhibition
of the degradation of kinins. It is not clear if newly available angiotensin II antagonists have the same antiproteinuric
and renoprotective effects.
Methods and Results. We compared the effect of an ACE inhibitor (enalapril, 0.4 mg/kg bw i.p. daily for 3 weeks)
and angiotensin II antagonist (losartan, 2 mg/kg bw in the same way) on experimental nephrotic syndrome induced
in rats by the administration of adriamycin (5 mg/kg bw i.v. in a single dose). To elucidate the potential differences
between these two drugs we also measured total malondialdehyde in blood and urinary excretion some eicosanoids
and their metabolites (TxB2, 6-keto-PGF1alfa, bicyclo-PGE2 and 8-isoprostane).
Proteinuria increased in adriamycin treated rats after 3 weeks from 0.18 ± 0.01 to 0.44 ± 0.14 g/mmol creat, p <
0.01. This increase was not prevented by losartan (increase from 0.18 ± 0.12 to 0.50 ± 0.11 g/mmol creat, p < 0.05),
but tended to be partly blunted by enalapril (increase from 0.20 ± 0.10 to only 0.32 ± 0.08 g/mmol creat, p < 0.05).
Similarly there was no increase of serum cholesterol, only in enalapril treated rats. On the other hand, both losartan
(1.27 ± 0.13 vs. 1.91 ± 0.30 mmol/l, p < 0.05) and enalapril (0.93 ± 0.06 mmol/l, p < 0.001) prevented adriamycin
induced increase of total MDA in serum, but urinary excretion of 8-isoprostane was increased in nephrotic rats
treated by losartan compared to controls. Enalapril induced increase of urinary excretion of bicyclo-PGE2 (4.32 ±
0.62 vs. 1.66 ± 0.81 ng/mmol creat, p < 0.001) was possibly mediated by kinins. There was no significant difference
in the urinary excretion of other eicosanoids between different groups, but proteinuria correlated positively with urinary excretion of 8-isoprostane (p < 0.01). Proteinuric rats had also significantly higher urinary excretion of
8-isoprostane than non-proteinuric rats (44.8 ± 7.1 vs. 26.7 ± 3.4 ng/mmol. creat, p < 0.05).
Conclusions. Our data suggest that proteinuria in adriamycin nephropathy may mainly depend on fre e radical
generation and the formation of 8-isoprostane. Haemodynamic parameters (glomerular pressure) do not seem to be
so important. The mild antiproteinuric effect of enalapril may suggest a contributory role of the inhibition of kinin
degradation in this model of nephrotic syndrome.
Key words:
losartan, enalapril, adriamycin, nephropathy, malondialdehyde, lipoperoxidation, eicosanoids, iso-
prostans.
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