Renal sodium handling in experimental diabetes: role of NO

Abstract

Recent studies have suggested that diabetes is a state of increased renal nitric oxide (NO) activity as assessed by urinary excretion of nitrites and nitrates (NO x ), and that NO synthase inhibitors reverse the increased glomerular filtration rate (GFR) observed in experimental diabetes. In addition to being a potent vasodilator in the renal vasculature, NO also plays a role in modulation of renal sodium excretion. To explore the role of NO in diabetes-associated alterations in renal excretory function, renal haemodynamic and sodium handling parameters were evaluated in conscious control (C) and streptozotocin diabetic rats (D) and correlated to the renal activity of NO, as assessed by urinary excretion of its metabolites NO x . To further explore this issue, the changes in renal haemodynamics and sodium handling were also assessed after NO synthase inhibition with a non-pressor dose of L-nitro-arginine-methyl-ester (L-NAME) and after administration of the NO donor, glyceryl trinitrate (GTN). Systolic blood pressure was not different between C and D rats. D rats exhibited marked hyperglycaemia ( P <0.001), and increases in GFR ( P <0.001), renal plasma flow, filtration fraction, urinary sodium excretion (U Na V, P <0.001), filtered load of sodium (FL Na , P <0.01), and a decrease in fractional reabsorption of sodium (FR Na , P <0.0001). In contrast, total reabsorption of sodium (TR Na ) was increased in D rats compared to C rats ( P <0.0001). The urinary excretion of NO was markedly increased in D rats ( P <0.01). Regression analyses performed in D rats revealed a close relationship between U Na V and GFR and a weaker correlation with urinary NO x . Although FR Na correlated only with urinary excretion of NO x , there was a strong relationship between TR Na and GFR. In contrast to D rats, control rats demonstrated only a relationship between TR Na and GFR and no other correlations were found, in D rats, NO inhibition with L-NAME (1 mg/kg body weight) resulted in a marked decrease in GFR and urinary NO x associated with decreases in FL Na and TR Na but did not influence FR Na . In contrast, in C rats the post-L-NAME decrease in NO x was not associated with significant changes in GFR and renal sodium handling. GTN-treated C rats exhibited a renal vasodilatory response and an increase in natriuresis and urinary NO x whereas no renal changes were observed in D rats during GTN administration. The present data indicate that changes in renal sodium handling before and after NO modulation in experimental diabetes are related to changes in GFR rather than to the renal activity of NO. Therefore, in contrast to the effects on renal haemodynamics, NO does not play an important role in the altered renal sodium handling observed in experimental diabetes.