Modulation of experimental cyclosporine nephrotoxicity by inhibition of thromboxane synthesis.
The clinical usefulness of Cyclosporine is limited by its intrinsic nephrotoxicity. A potential mechanism of CsA-mediated renal injury may involve an alteration in the prostaglandin-thromboxane (PG-TX) cascade. In our studies, pharmacological manipulation of the PG-TX system in normal and nephrotoxic animals was conducted using a specific thromboxane synthetase inhibitor U63,557A, and the cyclooxygenase inhibitor indomethacin. Administration of CsA 50 mg/kg/day for 7 days to Sprague Dawley rats resulted in a 99% increase in urinary thromboxane B2 excretion compared with controls (48.2 +/- 3.1 vs. 24.2 +/- 2.6 ng/24 hr, P less than 0.001), while plasma levels remained unchanged. Glomerular and tubular function was significantly reduced at this time, with a 48% decrease in creatinine clearance (CCr), and a 25% reduction in the fractional excretion of sodium (FeNa) (P less than 0.001). Histological injury included cortical tubular vacuolization and necrosis. Administration of indomethacin 8 mg/kg/day to both normal and CsA-treated rats resulted in a significant reduction in prostanoid excretion. Indomethacin alone had no adverse effect on glomerular function; however, when coadministered with CsA an exaggerated decrease in renal function was observed. CCr in this group fell by a further 27% compared with the CsA-50 group, while FeNa decreased by 76% (P less than 0.001). Histologic injury intensified, with an increase in vacuolization and necrosis. In contrast, coadministration of U63,557A with CsA prevented the rise in urinary TXB2 excretion, improved CCr by 20% (P less than 0.05), and restored FeNa to control levels. The severity of CsA-induced vacuolization was significantly diminished. Selective inhibition of thromboxane production may therefore be valuable in mitigating the clinical nephrotoxicity of CsA.
Petric
R
R
Department of Medicine, University Hospital, London, Ontario, Canada.
Freeman
D
D
Wallace
C
C
McDonald
J
J
Stiller
C
C
Keown
P
P
D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D003524:Cyclosporins / Q000633:toxicity*; D007213:Indomethacin / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013928:Thromboxane A2 / Q000096:biosynthesis*; D014661:Vasoconstriction / Q000187:drug effects
D001572:Benzofurans; D003524:Cyclosporins; D013928:Thromboxane A2; C039936:furegrelate; D007213:Indomethacin