Background: Ammonia is central to hepatic encephalopathy pathogenesis, inducing brain swelling and critically altering brain function through dysfunction of nitric oxide/cGMP signaling. Ornithine phenylacetate (OP) reduces brain water and ammonia in cirrhotic animals. This study aimed to determine if (i) eNOS activity is reduced in cirrhotic brains and whether this is associated with changes in asymmetric-dimethylarginine (ADMA- an endogenous eNOS inhibitor) and its regulating enzyme, dimethylarginine-dimethylaminohydrolase (DDAH1), and (ii) if these factors are restored by ammonia reduction using OP. Methods: Sprague-Dawley rats were studied 4-weeks after bile-duct ligation (BDL) (n=16) or sham-operation (n=8) and treated with placebo or OP (0.6gm/Kg) i.p. Measurements: Arterial and brain ammonia and plasma biochemistry using Cobas-Integra; Brain water measured using the dry weight technique; TNF by FACS bead assay; Plasma and brain ADMA and L-arginine analyzed by LCMS/tandem-MS; NOS activity measured radio-metrically and protein expression for eNOS, iNOS, DDAH-1 and 4HNE by Western Blotting. Results: BDL significantly increased arterial and brain ammonia (p<0.001), brain water (p<0.05), iNOS activity and expression and brain TNF (p<0.01), and these factors were reduced significantly by OP treatment. eNOS activity was significantly lower (p<0.05) and expression greater in BDL animals compared with sham and this was normalized in OP treated animals. Brain ADMA levels were significantly higher and brain DDAH-1 significantly lower in BDL compared with sham (p<0.05) and restored towards normal following treatment with OP. Conclusion: This study shows a marked abnormality of nitric oxide regulation in cirrhotic brains which can be restored by reduction in ammonia concentration using OP.
- Copyright © 2011, American Journal of Physiology- Gastrointestinal and Liver Physiology