Nitric oxide in streptozotocin-induced diabetes mellitus in rats

Abstract

1. The present study was performed to determine the relationship between diabetic glomerular hyperfiltration and nitric oxide as modulated by the chronic administration of L-arginine and/or N-omega-nitro-L-arginine, a known nitric oxide synthase inhibitor in streptozotocin-induced diabetic rats. 2. Normal rats and rats drinking hypertonic glucose (10%) were used as time-controlled groups. Six weeks after administration of streptozotocin the diabetic rats had significantly higher creatinine clearance (667 +/- 53 microliters min-1 100 g-1 body weight) than before and streptozotocin (456 +/- 38 microliters min-1 100 g-1 body weight, P < 0.005) and very high plasma (37.8 +/- 10.9 mumol/l) and urinary (3.492 +/- 0.179 nmol min-1 100 g-1 body weight) nitrite+nitrate (stable metabolites of nitric oxide) values compared with before streptozotocin administration [19.3 +/- 2.8 mumol/l (P < 0.001) and 0.420 +/- 0.051 nmol min-1 100 g-1 body weight (P < 0.001) respectively]. The 6-week diabetic rats had higher systolic blood pressure (124.2 +/- 2.9 mmHg, P < 0.05) than before streptozotocin (108 +/- 8 mmHg), but had a value similar to that of the hypertonic-glucose-drinking rats. 3. The diabetic rats supplemented with L-arginine did not show an increase in creatinine clearance and had a lower urinary excretion of nitrite+nitrate (0.999 +/- 0.27 nmol min-1 100 g-1 body weight, P < 0.005) than the respective untreated streptozotocin-induced diabetic rats. Creatinine clearance increased in the normal and glucose-drinking rats that received L-arginine. The administration of L-arginine resulted in significant reduction in blood pressure in all groups studied. The chronic nitric oxide synthase inhibitor resulted in high blood pressure, and in a significant decrease in creatinine clearance and urinary nitrite+nitrate excretion in all groups studied. In both diabetic and glucose-drinking rats, the L-arginine therapy resulted in significantly lower plasma and urinary glucose levels than in their respective untreated control groups. 4. The nitric oxide synthase inhibitor increased the plasma and urinary glucose concentration in both diabetic and glucose-drinking rats. 5. Our results indicate that diabetic rats are characterized by high plasma concentrations and elevated urinary excretion of nitrite+nitrate, suggesting a state of high nitric oxide production. The vascular response to nitric oxide in diabetic rats may be different at the glomerular and peripheral vascular bed.