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Dose-related cyclosporine-induced renal dysfunction is the most frequent adverse effect noted with this exciting immunosuppressive drug. To investigate pathogenetic factors involved, we studied renal tubular function and afferent arteriolar morphology during severe experimental cyclosporine-induced reduction in glomerular filtration rate. Pair-fed male rats were given cyclosporine 50 mg/kg or olive oil vehicle alone by gavage for periods of 3–14 days. Glomerular filtration rate declined progressively, reaching a nadir of 0.18±.05 ml/min/100 g vs. .86±.03 ml/min/100 g in controls at 14 days (P <0.001). Despite the severe reduction in glomerular filtration rate there was no difference in fractional sodium excretion, fractional lithium excretion, enzymuria, or in vitro renal cortical slice uptake of tetraethylammonium in cyclosporine and vehicle-treated animals. Light microscopy showed vacuolar changes without evidence of tubular necrosis at 7 and 14 days in cyclosporine-treated rats. Progressive decline in the diameter of the afferent arteriole was noted by scanning electron microscopy. By day 14 the lumenal diameter of afferent arterioles from cyclosporine-treated animals was 8.9±0.4 μm vs. 13.5±0.4 μm in controls (P <0.05). We conclude that afferent arteriolar vasoconstriction rather than direct tubular injury is a major pathogenetic factor in experimental cyclosporine nephrotoxicity.