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 diabe
tes has not been studied. To explore the hypothesis that diabetic vascular
dysfunction is in part caused by altered neuronal nitric oxide synthase act
ivity, systemic and renal hemodynamics were assessed before and after acute
inhibition of this enzyme with a specific inhibitor, S-methyl-L-thiocitruI
line, 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 compare
d with rats treated with losartan alone. Diabetic animals demonstrated high
er baseline glomerular filtration rates and filtration fractions. At a low
dose, the neuronal nitric oxide synthase inhibitor induced similar dose-dep
endent presser responses in control and diabetic rats. Losartan abolished t
he presser response in both groups. No changes in renal plasma flow or rena
l vascular resistance occurred in control rats. In contrast, diabetic rats
responded with significant renal vasoconstriction. At a high dose, the rena
l vasoconstriction was similar in both groups and was not affected by losar
tan. In conclusion, neuronal nitric oxide synthase-derived nitric oxide pla
ys a role in the control of systemic and renal hemodynamics in normal and d
iabetic rats. Diabetic rats are more sensitive to the inhibitor, suggesting
increased activity of this pathway in the diabetic kidney. Furthermore, re
nal responses in diabetic rats were attenuated by angiotensin II receptor b
lockade, whereas losartan alone induced hemodynamic changes that were oppos
ite those seen with neuronal nitric oxide synthase inhibition. This observa
tion implicates angiotensin II as an important modulator of this nitric oxi
de pathway in diabetes.