Role of neuronal nitric oxide synthase (NOS1) in the pathogenesis of renalhemodynamic changes in diabetes

Nitric oxide (NO) has been implicated in the pathogenesis of renal hemodyna mic changes in diabetes mellitus. However, the contribution of nitric oxide synthase (NOS) isoforms to intrarenal production of NO in diabetes remains unknown. To explore the role of NOS1 in the control of renal hemodynamics in diabetes, we assessed renal responses to inhibition of NOS1 with S-methy l-L- thiocitrulline (SMTC; administered into the abdominal aorta) in modera tely hyperglycemic streptozotocin-diabetic rats (D) and their nondiabetic ( C) and normoglycemic diabetic counterparts. The contribution of other NOS i soforms was also evaluated by assessing the responses to nonspecific NOS in hibition [N-G-nitro-L-arginine methyl ester (L-NAME)] in SMTC-treated diabe tic rats. The number of NOS1-positive cells in macula densa of D and C kidn eys was also evaluated by immunohistochemistry. D rats demonstrated elevate d glomerular filtration rate (GFR) compared with C. SMTC (0.05 mg/kg) norma lized GFR in D but had no effect in C. SMTC-induced reduction of renal plas ma flow (RPF) was similar in C and D. Normoglycemic diabetic rats demonstra ted blunted renal hemodynamic responses to NOS1 inhibition compared with hy perglycemic animals. Mean arterial pressure was stable in all groups. L-NAM E induced a further decrease in RPF, but not in GFR, in D rats treated with SMTC. Immunohistochemistry revealed increased numbers of NOS1-positive cel ls in D. These observations suggest that NOS1-derived NO plays a major role in the pathogenesis of renal hemodynamic changes early in the course of di abetes. NOS1 appears to be the most important isoform in the generation of hemodynamically active NO in this condition.