Effects of systemic inhibition of neuronal nitric oxide synthase in diabetic rats

Diabetes is associated with alterations in nitric oxide-mediated vasomotor function. The role of nitric oxide generated via the neuronal nitric oxide synthase pathway in the control of systemic and renal hemodynamics in diabetes has not been studied. To explore the hypothesis that diabetic vascular dysfunction is in part caused by altered neuronal nitric oxide synthase activity, systemic and renal hemodynamics were assessed before and after acute inhibition of this enzyme with a specific inhibitor, S-methyl-L-thiocitrulline, in control and diabetic rats. The interaction of this pathway and the renin-angiotensin system was studied in separate groups of rats pretreated with the angiotensin II receptor blocker losartan; these rats were compared with rats treated with losartan alone. Diabetic animals demonstrated higher baseline glomerular filtration rates and filtration fractions. At a low dose, the neuronal nitric oxide synthase inhibitor induced similar dose-dependent pressor responses in control and diabetic rats. Losartan abolished the pressor response in both groups. No changes in renal plasma flow or renal vascular resistance occurred in control rats. In contrast, diabetic rats responded with significant renal vasoconstriction. At a high dose, the renal vasoconstriction was similar in both groups and was not affected by losartan. In conclusion, neuronal nitric oxide synthase-derived nitric oxide plays a role in the control of systemic and renal hemodynamics in normal and diabetic rats. Diabetic rats are more sensitive to the inhibitor, suggesting increased activity of this pathway in the diabetic kidney. Furthermore, renal responses in diabetic rats were attenuated by angiotensin II receptor blockade, whereas losartan alone induced hemodynamic changes that were opposite those seen with neuronal nitric oxide synthase inhibition. This observation implicates angiotensin II as an important modulator of this nitric oxide pathway in diabetes.