Abstract 16227: The Hemodynamic Effects of Deletion of DDAH2 in Conscious Mice
Introduction: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS) that mediates numerous physiological processes. ADMA is metabolized by dimethylarginine dimethylaminohydrolayse (DDAH). DDAH has two isoforms, DDAH1 and DDAH2. Although the cardiovascular effects of DDAH1 expression has been widely investigation, direct evidence that DDAH2 is implicated in the regulation of cardiovascular response is still scarce.
Methods: The homozygous DDAH2 knockout mice and wild type C57/B6 littermates were recruited (n=7 in each group). A transmitter catheter (PA-C10, Data Science International) was inserted into left carotid artery until the tip reached the aortic arch. The animals were given one week for recovery. Baseline recordings were set in continuous mode over a period of 24 hours to sample arterial pressure and heart rate. Blood were harvested by tail bleeding for measurements of dimethylarginine and nitrite/nitrate concentration. Thereafter, they were fed with 0.1% L-arginine in drinking water for 3 days and then recorded in the same mode.
Results: DDAH2-/- animals had a significantly higher systolic blood pressure than wildtype littermates when they were in active phases (11.5±5.8mmHg higher). Treatment with 0.1% L-arginine dropped blood pressure in DDAH2-/- animals more than in wildtype ones (-6.7±1.2 vs. -2.3±1.2 mmHg). Plasma nitrite/nitrate concentration was significantly lower in the ddah2-/- group than in the wildtype group (22.03±2.16 vs. 43.87±7.45 μmol/l). Plasma ADMA concentrations tended to be higher DDAH2-/- animals without significance (0.64 ±0.02 vs. 0.62 ±0.03 μmol/l) and SDMA concentrations were of no difference between two groups (0.33±0.03 vs. 0.31±0.03 μmol/l). However, plasma L-NMMA concentration was elevated by over 40% in ddah2-/- mice (0.41 ±0.04 vs. 0.28 ±0.02 μmol/l).
Conclusion: We demonstrated for the first time that DDAH2 knockout animals have a hypertension phenotype. This was associated with an impact on methylarginine metabolisms and nitrite oxide signalling. A deletion of DDAH2 expression caused animals sensitive to exogenous source of nitrite oxide. Therefore, these findings indicate that DDAH2, as well as DDAH1, plays an active role in the cardiovascular regulation.
- © 2013 by American Heart Association, Inc.