Nitric oxide originating from NOS1 controls oxygen utilization and electrolyte transport efficiency in the diabetic kidney.

Nitric oxide (NO) is a potent regulator of both vascular tone and cellular oxygen consumption (Q(O(2)). Diabetic kidneys have reduced NO availability and increased Q(O(2)). However, the exact nitric oxide synthase (NOS) isoform regulating Q(O(2)), hemodynamics, and excretory function in the diabetic kidney remains unclear. We therefore investigated the effects of both selective neuronal NOS (NOS1) inhibition and nonselective NOS inhibition. Oxygen utilization, electrolyte transport efficiency [tubular Na(+) transport (T(Na))/Q(O(2))], renal blood flow (RBF), glomerular filtration rate (GFR), and mean arterial pressure (MAP) were measured in vivo in control and streptozotocin-diabetic rats before and after administration of the selective NOS1 inhibitor S-methyl-L-thiocitrulline (SMTC) or the nonselective NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). Diabetic rats had higher baseline Q(O(2)) and GFR than control rats, although RBF was similar in the groups. SMTC and L-NAME increased Q(O(2)) and reduced T(Na)/Q(O(2)) only in the diabetic animals, whereas both inhibitors increased MAP and reduced RBF in both groups. GFR was reduced by L-NAME, but SMTC had no effect in either group. Carbachol increased RBF and decreased MAP in SMTC-treated rats, whereas it had no effect in L-NAME-treated rats, indicating that SMTC selectively inhibited NOS1. In conclusion, NO regulates RBF and GFR similarly in both control and diabetic rats. However, selective NOS1 inhibition increased Qo(2) and reduced T(Na)/Q(O(2)) in the diabetic rat kidney, indicating a pivotal role of NO produced by NOS1 in maintaining control of Q(O(2)) and tissue oxygenation in these kidneys.