Nitric Oxide (NO) is an important mediator of cardiovascular function and its impaired synthesis is a feature of many cardiovascular diseases. Raised concentrations of an endogenous inhibitor of NO synthesis, asymmetric dimethylarginine (ADMA), are associated with renal failure, hypertension, heart failure and impaired angiogenesis. ADMA is generated during protein turnover and metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). The significance of this pathway in vivo is unknown. This series of studies demonstrates that the metabolism of ADMA by DDAH influences NO synthesis in vitro and in vivo and that this pathway is likely to be important in man. An important regulator of tissue development and remodelling, all-trans-retinoic acid (atRA), has been shown to upregulate an isoform of DDAH, DDAH2, and regulate NO synthesis in vitro. Using a novel transgenic mouse model, it has been shown that the overexpression of DDAH in vivo can increase NOS activity and lower blood pressure. A mouse model of unilateral hindlimb ischaemia has been used to demonstrate that ischaemia can increase ADMA formation and also upregulate DDAH expression in order to restore ADMA levels to baseline and potentiate NO synthesis. Finally, a randomised, double-blind, placebo-controlled study demonstrates that an acute systemic increase in ADMA produces adverse cardiovascular effects in humans, both at rest and during exercise. These results support a causal role relationship between raised ADMA levels and cardiovascular dysfunction. The data also indicates that ADMA is metabolised by DDAHs extensively in humans in vivo; humans generate approximately 300 mol of ADMA per day, of which approximately 250 mol is metabolised by DDAHs.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:416616 |
| Date | January 2004 |
| Creators | Achan, Vinod |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1446828/ |
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