Role of Endothelium-Derived Nitric Oxide in the Pathogenesis of the Renal Hemodynamic Changes of Experimental Diabetes

To evaluate the role of nitric oxide (NO) in diabetic hyperfiltration, renal hemodynamic changes and changes in urinary excretion of NO₂/NO₃ in response to the NO inhibitor nitro-L-arginine methyl ester (L-NAME) and the NO-donating agent glyceryl trinitrate (GTN) were investigated in conscious streptozocin-induced diabetic (D) and age-matched control (C) rats. In all experiments, D rats demonstrated increased glomerular filtration rate (GFR), renal plasma flow (RPF), polyuria, and an increased urinary sodium excretion when compared with C rats. An intravenous bolus of low-dose L-NAME (1 mg/kg body wt) increased modestly systolic blood pressure (sBP) in C rats but had no effect on sBP in D rats. _L-NAME induced a marked decrease in GFR and RPF in D rats with no change in filtration fraction (FF). In C rats, no change in GFR was observed, and RPF decreased, resulting in a rise in FF. A supramaximal dose of _L-NAME (10 mg/kg body wt) increased sBP in C and D rats to a similar degree. With high-dose L-NAME, GFR decreased in D but not in C rats. There was a greater decrease in RPF in D rats when compared with C animals. An intravenous infusion of GTN induced a modest decrease in sBP in both C and D rats (P < 0.01). There were no changes in GFR and RPF in D rats, but in the C group, GTN increased RPF (P < 0.05) with a tendency for a rise in GFR (P = 0.09). Basal urinary NO₂/NO₃ excretion was increased in D rats in all experiments. A decrease in urinary NO₂/NO₃ levels was observed after low-dose L-NAME in D rats, with a similar trend after high-dose L-NAME. NO such changes were observed in C rats. GTN infusion had no effect on urinary NO₂/NO₃ excretion in D rats but increased urinary NO₂/NO₃ levels in C rats to levels that were not statistically different from those in D rats. These studies suggest that increased renal production and/or sensitivity to endothelium-derived relaxing factor/NO may play a role in the genesis of diabetic hyperfiltration.