Biochemistry and Molecular Biology Inverse Relationship Between the Intraretinal Concentration of Bioavailable Nitric Oxide and Blood Glucose in Early Experimental Diabetic Retinopathy

Citation: Guthrie MJ, Osswald CR, Kang-Mieler JJ. Inverse relationship between the intraretinal concentration of bioavailable nitric oxide and blood glucose in early experimental diabetic retinopathy. Invest Ophthalmol Vis Sci. 2015;56:37-44. DOI:10. 1167/iovs.14-15777 PURPOSE. To directly measure in vivo retinal nitric oxide (NO) concentration in experimental early diabetic retinopathy and correlate measurements with blood glucose to determine how intraretinal NO changes with severity of diabetes. METHODS. Long-Evans rats were made diabetic with streptozotocin (STZ). Three weeks post STZ injection, intraretinal NO concentration profiles were recorded using a dual NO/ electroretinogram microelectrode. Diabetic profiles were compared with profiles from healthy controls, healthy rats injected with the NO synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME), and healthy rats that received acute glucose injections (''acute hyperglycemia''). The NO values at the retina/RPE boundary (100% retinal depth) and retinal surface (0% depth) were analyzed for correlation with blood glucose. RESULTS. The average NO concentrations in the outer retina, inner retina, and vitreous humor of mild diabetic rats (250-400 mg/dL) were significantly higher than controls by 73%, 47%, and 70%, respectively. The average NO concentrations in the outer retina, inner retina, and vitreous humor of severe diabetic rats (500-600 mg/dL) were lower than controls, with NO at 41%, 36%, and 36% of controls, respectively, similar to L-NAME-treated eyes (38%, 36%, 20% of control). The NO levels in moderate diabetic rats (400-500 mg/dL) and acute hyperglycemia rats were similar to controls. The NO was significantly and inversely correlated with blood glucose for diabetic rats at 100% depth (R ¼ À0.91) and 0% depth (R ¼ À0.79) but not for acute hyperglycemia rats. CONCLUSIONS. The higher-than-control level of NO in mild diabetic rats and lower-than-control level in severe diabetic rats show that severity of diabetes is an important factor when measuring the bioavailability of NO in diabetic retinopathy