In a previous study, we demonstrated that doxazosin (DZN), an alpha(1)-adrenergic blocker, prevented proteinuria in streptozotocin diabetic rats. In this study, we investigated whether DZN would lower established proteinuria by improving glomerular sclerosis in spontaneously hypertensive corpulent rats with type 2 diabetes mellitus. DZN treatment was compared with treatment with angiotensin-converting enzyme inhibitor, lisinopril (LIS) alone, and DZN in combination with LIS. Combination therapy was used to examine any additive effect of either drug alone in the reduction of proteinuria and glomerular sclerosis. Both male and female rats age 6 months with established proteinuria were used. The rats were allocated randomly to 1 of 4 groups: untreated, DZN treated, LIS treated, or a combination of DZN and LIS treatment. Drug treatment was continued for 16 weeks. The results show that (1) either drug alone or in combination significantly lowered systolic blood pressure; (2) DZN, LIS, or combination therapy reduced albuminuria at 16 weeks of treatment from baseline by 38.61+/-5.77%, 30.70+/-4. 21%, and 42.17+/-4.77% (mean+/-SE), respectively. No difference in albuminuria was observed among the 3 groups of rats; (3) the fractional mesangial area, which was 20.55+/-3.77% in untreated rats, was significantly reduced to 11.18+/-1.32% in DZN-treated rats, with a further reduction to 8.72+/-0.64% in LIS-treated rats and to 3.48+/-0.35% in rats treated with DZN+LIS; and (4) DZN but not LIS significantly improved plasma glucose levels in spontaneously hypertensive corpulent rats (untreated 21.06+/-0.97 mmol/L versus DZN treated 15.81+/-0.93 mmol/L or DZN+LIS treated 17.38+/-1.10 mmol/L; P<0.025 to 0.005). Thus, the data suggest that 16-week treatment with either DZN or LIS improves established proteinuria and glomerular sclerosis, but combination therapy is superior to either DZN or LIS alone in preventing glomerular sclerosis in type 2 diabetic rats with hypertension.