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.