Aim This study was designed to test the hypothesis that OP has additional actions on the key ammonia regulating enzymes glutamine synthetase (GS) and glutaminase (GA), which results in the observed ammonia lowering effect of OP in cirrhotic rats.
Method 11.53 g: 4 sham operated, and 11 BDL. 5 BDL's received OP (5 days, IP 0.6 g/kg), 5 BDL's received ornithine (5 days, IP 0.6 g/kg), 5 BDL's received phenylacetate (5 days, IP 0.6 g/kg) and six received saline (IP). We measured plasma levels for: ammonia and standard biochemical markers. Expressions of GS, GA and ornithine amino transferase (OAT) were determined by Western blot (expressed as a % of sham values) and activity by end-point methods in liver, kidney, gut, muscle and lung.
Results Plasma ammonia was decreased in BDL-OP rats vs BDL-saline (58.97±6.02 vs 106.2±20.56 μmol/l). BDL-OP rats showed increased GS expression in liver (66% BDL-OP vs 55% BDL-saline; p<0.01) and showed further increased levels in the muscle (153% BDL-OP vs 142% BDL-saline). OP prevents the BDL related increases in glutaminase expression (124% vs 163%; p<0.05) and activity (0.45±0.16 mIU/mg protein BDL-OP vs 1.14±0.046 mIU/mg protein BDL-saline; p<0.01) in gut. We demonstrated that this prevention is due to effect of ornithine in glutaminase activity (0.46±0.17 mIU/mg protein BDL-O vs BDL-saline; p<0.05) and not to phenylacetate. OP treatment increased OAT expression in muscle (142 %BDL-OPvs.114% BDL-saline; p<0.01) and lung (103%BDL-OP vs 127%BDL-saline; p<0.01).
Conclusion OP treatment in BDL rats increased the conversion of glutamate to glutamine by stimulation of OAT and GS in the muscle and also resulted in normalisation of glutaminase expression and activity in the gut, indicating that OP effectively restricts the production of in vivo ammonia in a cirrhotic model explaining the lack of stoichiometry between ammonia reduction and excretion of phenylacetylglutamine. In summary, the mechanism by which OP reduces ammonia in cirrhosis is by increasing glutamine synthesis (action of “O”) and its excretion as phenylacetylglutamine (action of “P”) and concomitantly normalising gut glutaminase activity (action of “O”), demonstrating synergistic effect of “O” and “P”.
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