L-arginine-nitric oxide pathway-related metabolites in the aqueous humor of diabetic patients

PURPOSE. Nitric oxide (NO) is an important signal-transduction molecule that plays a significant role in the regulation of cardiovascular functions. In the L-arginine-NO pathway, NO synthase (NOS) converts L-arginine (L-Arg), the only known biologic substrate for NO formation, to NO and L-citrulline (L-Cit). Excessive NO production mediated by the inducible isoform of NOS has been implicated in the pathogenesis of various diseases. In the present study it was hypothesized that in vitreoretinal disorders such as diabetic retinopathy the production of L-Arg-NO pathway-related metabolites may be upregulated as a result of increased NO generation. METHODS. From 20 eyes of nondiabetic subjects and 22 eyes of diabetic patients with (n = 14) and without (n = 8) diabetic retinopathy, undiluted samples of aqueous humor were drawn before cataract surgery. Levels of L-Arg, L-Cit, and the specific NOS byproduct NG-hydroxy-L-arginine (HOArg) were measured by high-performance liquid chromatography. RESULTS. L-Arg, L-Cit, and HOArg were detected in all aqueous humor samples from diabetic and nondiabetic patients (n = 42). Comparison of HOArg levels in nondiabetic and diabetic subjects showed significantly higher levels in diabetic patients (P = 0.002). Concentrations of HOArg were higher in samples from patients with (P = 0.005) and without diabetic retinopathy (P = 0.033) than in control subjects. No statistically significant differences were observed in L-Arg or L-Cit levels. CONCLUSIONS. Elevated levels of HOArg in the aqueous humor of diabetic patients reflect the possible role of NO as a significant factor in the regulation of retinal vascular functions and intraocular proliferative changes in diabetes mellitus in vivo. The control of intraocular NO production may constitute a potential therapeutic approach in diabetic retinopathy.