Background. Cyclosporine (CsA)-induced nephrotoxicity may be due to in
trarenal vasoconstriction and glomerular hypoperfusion. Several factor
s, including endothelin and prostanoids, are suggested mediators of th
is response. Recent evidence suggests that CsA leads to increased oxyg
en-derived free radical (ODFR) production and lipid peroxidation in re
nal tissue. Whether this leads to alterations in renal vessel reactivi
ty is unclear. Lazaroids, such as U74389G, are radical-quenching antio
xidants that inhibit ODFR-induced lipid peroxidation and may improve r
enal function after ischemia and reperfusion. We hypothesized that ODF
Rs contribute to CsA-induced alterations of the renal microcirculation
. Methods. Rat hydronephrotic kidneys were studied by video microscopy
. Interlobular arteriolar diameter and flow, afferent and efferent art
eriolar diameters, and cardiac output were measured at 15-min interval
s for 120 min. U74389G or its vehicle was infused 15 min before topica
l application of CsA to the kidney. The results were compared with U74
389G alone and normal saline. Results. CsA administration caused renal
microvascular vasoconstriction (10-25% below baseline) and hypoperfus
ion (35% below baseline). Both vasoconstriction and hypoperfusion were
significantly attenuated by U74389G (5-8% and 20% below baseline, res
pectively). Conclusions. Inhibition of lipid peroxidation by U74389G m
aintained renal blood flow during acute CsA administration. These data
suggest that ODFRs are involved in the renal microvascular response t
o CsA. Inhibition of ODFR-induced lipid peroxidation may help prevent
CsA-induced glomerular hypoperfusion. Lazaroids may prove an effective
adjunct in reducing CsA-induced nephrotoxicity.