The relationship of urinary thromboxane excretion to cyclosporine nephrotoxicity.
Alterations in renal prostaglandin production have recently been postulated to modulate the decrease in renal blood flow associated with cyclosporine nephrotoxicity. In particular, increases in renal production of the potent vasoconstrictor thromboxane A2 have been implicated in the pathogenesis of this disorder. The present study was undertaken to explore the relationship between alterations in urinary thromboxane B2 excretion (UTxB2V) and CsA nephrotoxicity in two rat models. Male Sprague-Dawley (SD) rats were treated for 14 days with CsA 50 mg/kg/day (n = 8) or olive oil (C) (n = 9) by gavage. Creatinine clearance (Ccr), urine flow (V), and urinary excretion rates of sodium, N-acetyl-beta-D-glucosaminidase (NAG), glucose, and TxB2 were determined before and after treatment. A similar study was conducted using Fischer rats (CsA: n = 10, C: n = 13). In Fischer rats, CsA caused a 35% decrease in Ccr (P = 0.01), a 33% decrease in sodium excretion (P = 0.02), and a greater than 2-fold increase in NAG excretion (P = 0.03), while V, glucose excretion, and UTxB2V did not change. Although similar changes in sodium and NAG excretion were seen after CsA administration in SD rats, Ccr was not affected. Additional findings in SD rats included a 3-fold increase in V (P less than 0.01), a 24-fold increase in glucose excretion (P = 0.03), and a 5-fold increase in UTxB2V (P = 0.04). Thus, Fischer rats developed CsA nephrotoxicity in the absence of increased UTxB2V. In contrast, SD rats failed to develop nephrotoxicity despite a marked increase in UTxB2V. We conclude that changes in renal TxA2 production are unrelated to the development of CsA nephrotoxicity.
Schnabel
F R
FR
Department of Surgery, State University of New York-Health Science Center, Brooklyn.
Wait
R B
RB
Kahng
K U
KU
D000118:Acetylglucosaminidase / Q000652:urine; D000818:Animals; D015415:Biomarkers / Q000652:urine; D003404:Creatinine / Q000378:metabolism; D003524:Cyclosporins / Q000633:toxicity*; D006029:Glycosuria; D007668:Kidney / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains; D012016:Reference Values; D012964:Sodium / Q000652:urine; D013929:Thromboxane B2 / Q000652:urine*
D015415:Biomarkers; D003524:Cyclosporins; D013929:Thromboxane B2; D012964:Sodium; D003404:Creatinine; D000118:Acetylglucosaminidase