Inducible Nitric Oxide Synthase and L-Arginine Optimizes Nitric Oxide Bioavailability in Ischemic Tissues Under Diabetes Mellitus Type 1.

Abstract

The mechanisms influencing the balance of nitric oxide (NO) bioavailability in tissues are negatively affected under diabetic and also under ischemic conditions. Free tissue transplantation for diabetic patients has to deal with both ischemic and diabetic circumstances, which lead to a significantly decrease in providing NO, thus increasing ischemia-reperfusion injury. In previous studies, we could prove that enhancing NO bioavailability leads to attenuated ischemia-reperfusion injury macrocirculatory and microcirculatory alterations in healthy and also in diabetes type 2 rats. This study is evaluating the role of inducible nitric oxide synthase in different dosages and L-arginine under diabetes type 1 conditions. Diabetic type 1 conditions were established via streptozotocin over a period of 4 weeks and verified via blood sugar, insulin, and C-peptide levels. Vascular pedicle isolated rat skin flap model that underwent 3 hours of ischemia was used. At 30 minutes before ischemia, normal saline, inducible nitric oxide synthase (NOS) (1/2 IE), and L-arginine (50 mg/kg body weight) were administered systemically. Ischemia/reperfusion (I/R)-induced alterations were measured 5 days after the operation. The inducible NOS (iNOS) attenuated I/R-induced alterations under diabetic type 1 conditions significantly with vitality rates of 16.1% compared with control group (5.5%). Best results could be achieved with the combination of iNOS (1 IE) and L-arginine displaying vitality rates of 43%. Increased dosage of inducible nitric oxide (2 IE) led to decreased vitality rates (22.2%/27.4% without/with L-arginine). Supporting the mechanisms of NO bioavailability via exogenous application of iNOS and L-arginine significantly attenuated I/R-induced alterations in a skin flap rat model. This pharmacologic preconditioning could be an easy and effective interventional strategy to uphold conversation of L-arginine to NO even on ischemic and type 1 diabetic conditions.