Abstract 251: Endogenous Endocrine Function of Cardiac-derived Nitric Oxide Yields Distant Organ Protection Against Ischemic Injury
Background: eNOS-derived nitric oxide (NO) has long been considered a paracrine signaling molecule only capable of affecting nearby cells due to its short half-life in blood (<2ms). We have recently shown that nitrite, previously thought to be an inert oxidation product of NO, is an important storage form converted to NO under hypoxic conditions via reductase activity. Currently, no studies have revealed endogenously generated NO to possess a clearly defined endocrine function, we therefore evaluated whether generation of NO in the heart could modulate remote physiological actions.
Methods: Mice with cardiac-specific (αMHC promoter) eNOS overexpression (CS-eNOS-Tg) and WT littermates were analyzed for NO metabolites in the heart, plasma, and liver (NO2−/NO3− - ion chromatography; nitroso/NO-heme - gas phase chemiluminescence). WT and CS-eNOS-Tg mice were subjected to 60 min hepatic ischemia and following 5 hr reperfusion (IR) serum ALT and AST were analyzed.
Results: Overexpression of eNOS restricted to the heart resulted in a significant increase in nitrite in the heart (2.2 fold), plasma (3.2 fold) and liver (6.5 fold). CS-eNOS-Tg displayed a significant reduction in hepatic IR injury (4.3 fold reduction in ALT and a 3.5 fold reduction in AST).
Conclusions: This represents the first report demonstrating that eNOS-derived NO is transported in the blood and stored in remote organs. Importantly, increases in nitrite levels resulted in protection against IR injury. These findings suggest NO possesses endocrine function via transport of nitrite in the blood to distant organs and that transported nitrite exhibits physiological activity.