PREVENTION OF EXPERIMENTAL CYCLOSPORINE NEPHROTOXICITY BY DIETARY SUPPLEMENTATION WITH LSL-90202, A LYSINE SALT OF EICOSAPENTAENOIC ACID - ROLE OF THROMBOXANE AND PROSTACYCLIN IN RENAL TISSUE
J. Torras et al., PREVENTION OF EXPERIMENTAL CYCLOSPORINE NEPHROTOXICITY BY DIETARY SUPPLEMENTATION WITH LSL-90202, A LYSINE SALT OF EICOSAPENTAENOIC ACID - ROLE OF THROMBOXANE AND PROSTACYCLIN IN RENAL TISSUE, Nephron, 67(1), 1994, pp. 66-72
Cyclosporine (CsA) nephrotoxicity is partially mediated by renal vasoc
onstriction due to an imbalance between vasodilator and vasoconstricto
r eicosanoids. LSL 90202 is a purified lysine salt of eicosapentaenoic
acid which is a known inhibitor of renal eicosanoid synthesis. The ai
m of the present work was to determine if chronic dietary supplementat
ion with LSL 90202 prevented CsA nephrotoxicity and to establish the r
ole of thromboxane and prostacyclin in renal tissue. Thirty-three male
Sprague-Dawley rats were divided into 4 groups: group 1, CsA in olive
oil (n = 10);group 2, isovolumetric olive oil (n = 7);group 3, CsA in
olive oil plus LSL 90202 (n = 8);group 4, isovolumetric olive oil plu
s LSL 90202 (n = 8). CsA and LSL 90202 were given at 20 mg/kg/day. Wei
ght and creatinine clearance (CrCl) were determined before and on days
14 and 30. On day 30 whole-blood CsA was determined and renal tissue
processed for renal malondialdehyde, thromboxane B2 and 6-keto-PGS(1 a
lpha) measurement and for conventional histology. CrCl was severely re
duced in the CsA in olive oil group compared to olive oil and LSL 9020
2 control groups. On day 30, CrCl in the CsA in olive oil plus LSL 902
02 group showed a slight decrease, but the mean CrCl was significantly
higher than in the CsA in olive oil group. Trough whole blood CsA lev
els were not significantly different in bath groups given the drug. No
morphological differences were found between groups. Renal content of
thromboxane B2 and 6-keto-PGF(1 alpha) (the stable metabolites of thr
omboxane A2 and prostacyclin, respectively) was higher in CsA in olive
oil group than in olive oil control group. In contrast, both eicosano
ids were similarly low in both groups receiving LSL 90202. The differe
nce between group 1 and group 3 was statistically significant. In summ
ary, our results suggest that LSL 90202 modifies CsA nephrotoxicity an
d that its benefitial effect may be due to its influence on intrarenal
biosynthesis of thomboxane A2 and prostacyclin.