Both functional and structural damage characterize nephrotoxicity due to cyclosporine (CsA) with accumulating evidence for dissociation of mechanisms that lead to each of these processes. We studied the role of endothelin (Et) and angiotensin II (AII), since each of these peptides can modulate vasoconstriction as well as parenchymal destruction. Salt-depleted rats were treated with daily CsA (15 mg/kg s.c.) for 5 weeks (group 1, CsA, n = 13). Separate groups of CsA-treated rats received either a combined antagonist of both EtA/EtB receptors (group 2, CsA+aEtA/B, 100 mg/kg/day p.o., n = 6) or angiotensin I-converting enzyme inhibitor (group 3, CsA+ACEI, enalapril 200 mg/L drinking water, n = 8). Glomerular filtration rate (GFR) was assessed by creatinine clearance (Ccr) in conscious rats at 3 and 5 weeks. At 3 weeks, serum creatinine was 1.5 +/- 0.1 mg/dl in group 1 rats, 1.2 +/- 0.2 mg/dl in group 2 rats (P < 0.05 vs. CsA), and 2.3 +/- 0.8 mg/dl in group 3 rats. Ccr was 0.87 +/- 0.08 ml/min in group 1. In group 2, GFR was remarkably preserved (1.14 +/- 0.11 ml/min, P < 0.05 vs. group 1). By contrast, GFR in group 3 rats was lower (0.31 +/- 0.08 ml/min) than either aEtA/B-treated or even CsA-treated rats (P < 0.0005 vs. group 1, P < 0.0005 vs. group 2). At 5 weeks, the same pattern emerged; serum creatinine was 2.5 +/- 0.2 mg/dl in group 1, 1.2 +/- 0.1 in group 2 (P < 0.0005 vs. CsA), and 3.4 +/- 0.9 in group 3 (P < 0.025 vs. CsA+aEtA/B). Ccr had decreased dramatically in CsA-treated rats to 0.18 +/- 0.03 ml/min. GFR was preserved in CsA+aEtA/B rats (0.51 +/- 0.03 ml/min, P < 0.0005 vs. group 1), while profound hypofiltration was apparent in CsA+ACEI rats (0.12 +/- 0.03 ml/min, P < 0.0005 vs. group 2). In salt-depleted control animals, GFR was 0.62 +/- 0.02 ml/min. Despite striking functional preservation in response to antagonism of Et receptors, tubular vacuolization/dilatation, as well as arteriolopathy, was not different among the CsA-treated groups. Tubulointerstitial fibrosis was also not different between CsA and CsA+aEtA/B rats (on a 0-4 scale, 1.05 +/- 0.14 vs. 0.87 +/- 0.14, P = NS). In contrast, both tubular vacuolization/dilatation and interstitial fibrosis were significantly greater in all CsA-treated groups compared with salt-depleted controls. However, in the CsA+ACEI group that had the most severe hypofiltration at each time point, tubulointerstitial fibrosis was 0.69 +/- 0.06 (P < 0.05 vs. CsA).(ABSTRACT TRUNCATED AT 400 WORDS)