Cause of variable therapeutic efficiency of angiotensin converting enzyme inhibitor on glomerular lesions. We tested the effect of angiotensin I converting enzyme inhibitor (ACEI) on established glomerular sclerosis. Starting eight weeks after subtotal nephrectomy (sNPX), rats were given enalapril for four weeks in a dose of 50 (Group II, N = 5) or 200 mg/liter drinking water (Group III, N = 5). A third group of sNPX rats not given ACEI served as control (Group I, N = 10). Glomerular sclerosis index (SI, 0 to 4 scale) was assessed three-dimensionally on serial thin sections for individual glomeruli at biopsy (Bx, 8 weeks), and divided into four different ranks of severity and compared to autopsy (Ax, 12 weeks). In Group I control rats, 48% of the glomeruli at Bx had SI between 0 and 1 (rank 1, average: 0.49 ± 0.06), 36% between 1 and 2 (rank 2, average: 1.53 ± 0.06), 9% between 2 and 3 (rank 3, average: 2.45 ± 0.12) and 7% between 3 and 4 (rank 4, average: 3.54 ± 0.10). Glomeruli of the same rats at Ax were ranked according to severity of sclerosis, and then divided into percentile groups, corresponding to the percent of distribution at Bx. The 48% least sclerotic glomeruli at Ax had average SI of 0.69 ± 0.08, the next 36% 2.58 ± 0.11, and next 9% 3.97 ± 0.02 and the most sclerotic 7% 4.00 ± 0.00. Thus, sclerosis advanced during the last four weeks after biopsy in all glomeruli, with more accelerated progression occurring toward later stages of sclerosis. The Bx and Ax specimens of Group II rats were analyzed in an identical fashion, showing virtually no appreciable increase in SI from Bx to Ax in glomeruli with SI < 2.0 at Bx. In contrast, SI increased in the most sclerotic glomeruli as much as that found in Group I control rats. SI at the whole kidney level, assessed on a single thin section, in Group I increased from Bx to Ax, on average by 176 ± 58% (P < 0.005). SI also increased in Group II, but to a significantly lesser degree, on average by 49 ± 17%. More remarkably, whole kidney SI decreased markedly and significantly in two Group III rats by 57 to 71% (on average 12 ± 24% reduction for all). From 8 to 12 weeks both systemic and glomerular pressures were normalized (∼112 mm Hg and ∼52 mm Hg, respectively) in Group II and Group III, contrasting the typically elevated values in Group I (∼180 mm Hg and ∼63 mm Hg). These results indicate that ACEI exerts variable effect on established glomerular sclerosis even within the same kidney. Thus, whereas ACEI has little or no effect on glomeruli with advanced sclerosis, it effectively preserves the structure of glomeruli with early or no sclerotic lesions. Moreover, ACEI in dosages in excess of required antihypertensive dose imparts additional benefit to glomerular structure, having a potential to reverse early glomerular lesions.