SummaryWe have previously shown that long-term administration of aminoguanidine, an inhibitor of advanced glycosylation product formation, reduces the extent of experimental diabetic retinopathy in the rat by 85 %. In order to determine whether the residual retinopathy that developed despite aminoguanidine was attributable to advanced glycation endproduct formation, a time-course study was performed in three different groups of male Wistar rats: non-diabetic controls (NC), streptozotocin-diabetic controls (DC) and streptozotocin-diabetic rats treated with aminoguanidine HCL, 50 rag/100 ml drinking water (D-AG). Eyes were obtained at 24, 32, 44 and 56 weeks of diabetes/treatment duration and morphologic evaluation was done on retinal digest preparations. At 56 weeks, retinal basement membrane thickness was additionally measured. After 24 weeks of diabetes, the number of acellular capillaries was significantly elevated in DC (44.6 + 5.7/mm 2 of retinal area, NC 19.6 + 4.9; p < 0.001) and increased continuously over time (DC 56weeks 87.4+ 15.1; p < 0.001 vs DC 24 weeks). In contrast, acellular capillaries in D-AG increased over the first 24 weeks and then remained constant for the rest of the study (D-AG 24 weeks 35.7 + 5.18; p < 0.01 vs NC 24 weeks and NS vs DC 24 weeks; D-AG 56 weeks 42.0 + 6.20; p NS vs D-AG 24 weeks). Diabetes-associated pericyte loss (DC 24 weeks 2310 + 170/mm 2 of capillary area; NC 24 weeks 3120+190; p<0.001; DC 56 weeks 1570+230; NC 56 weeks 2960+50; p <0.001) was significantly prevented by aminoguanidine after diabetic-like changes over the initial 24 weeks (D-AG 24 weeks 2450 + 75; p NS vs DC 24 weeks; D-AG 56 weeks 2350 + 90; p < 0.001 vs DC 56 weeks). At 56 weeks, aminoguanidine treatment was associated with a 67.4 % reduction in retinal basement membrane thickening. This time-course study demonstrates that aminoguanidine prevents the progression of experimental diabetic retinopathy, and suggests that non AG-inhibitable mechanisms are involved in the initial phase of diabetic retinopathy. [Diabetologia (1995) 38: 269-273]