EFFECT OF DILTIAZEM ON GLOMERULAR HEPARAN-SULFATE AND ALBUMINURIA IN DIABETIC RATS

Calcium entry blockers, particularly diltiazem, have been shown to low er not only systemic blood pressure but also improve proteinuria in no n-insulin-dependent diabetic patients. The presence of proteinuria is attributed to the loss of glomerular heparan sulfate, which confers a negative charge on the basement membrane. In the present study, we eva luated the efficacy of diltiazem in lowering blood pressure and protei nuria in diabetic rats and also examined the possibility that diltiaze m prevents proteinuria through glomerular preservation of heparan sulf ate. Diabetes was induced in male Wistar rats by streptozotocin (60 mg /kg). One group of diabetic rats was treated with diltiazem (25 mg/L) in drinking water for 20 weeks. Another group of diabetic rats and a g roup of nondiabetic rats were given tap water only. Systolic blood pre ssure was measured at 4, 8, 12, and 20 weeks. Urinary excretion of alb umin was done at 4, 8, 12, 16, and 20 weeks. At the end of 20 weeks, a ll rats were killed, kidneys were removed, and glomeruli were isolated . Total glycosaminoglycan and heparan sulfate synthesis were determine d by incubating glomeruli in the presence of [S-35] sulfate. Diltiazem lowered blood pressure significantly in diabetic rats at 8, 12, and 2 0 weeks. Diabetic glomeruli synthesized less total glycosaminoglycan a nd heparan sulfate than glomeruli from normal rats. Characterization o f heparan sulfate by ion-exchange chromatography showed that the fract ion eluted with 1 M NaCl was significantly lower and the fraction elut ed with 1.25 M NaCl significantly higher in diabetic than in normal ra ts. Diltiazem therapy returned not only glomerular synthesis but also various fractions of heparan sulfate to normal. Urinary albumin excret ion was significantly higher in diabetic than in normal rats; diltiaze m therapy significantly lowered albuminuria in diabetic rats. The data suggest that diltiazem therapy prevents albuminuria through preservat ion of glomerular heparan sulfate in diabetic rats.