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OtherTOXICOLOGY

Treatment of Cirrhotic Rats withl-Ornithine-l-Aspartate Enhances Urea Synthesis and Lowers Serum Ammonia Levels

Rolf Gebhardt, Gerhard Beckers, Frank Gaunitz, Wolfram Haupt, Dirk Jonitza, Sabine Klein and Ludger Scheja
Journal of Pharmacology and Experimental Therapeutics October 1997, 283 (1) 1-6;
Rolf Gebhardt
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Gerhard Beckers
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Frank Gaunitz
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Wolfram Haupt
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Dirk Jonitza
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Sabine Klein
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Ludger Scheja
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Abstract

CCl4-induced cirrhosis of rats was used for studying the influence of l-ornithine-l-aspartate (OA) on hyperammonemia. OA given to cirrhotic rats (2 g/kg daily) for 2 wk slightly increased net body weight and led to a significant increase in plasma urea levels and a decrease in plasma ammonia levels. Serum concentrations of glutamate, glutamine and arginine decreased significantly. In the livers of the OA-treated rats the activities of carbamoylphosphate synthetase I and arginase increased by 30 and 40%, respectively, approaching normal levels. No change in the activities of the other urea cycle enzymes as well as of glutamate dehydrogenase, glutaminase and glutamine synthetase was found. The negative correlation between glutamine synthetase activity and plasma ammonia levels reported previously for cirrhotic rats (Gebhardt and Reichen, Hepatology 20:684–691, 1994) was corroborated for cirrhotic animals not treated with OA, but was no longer apparent in OA-treated cirrhotic rats. Despite this improvement, plasma ammonia levels still varied considerably reflecting the variable accessibility and activities of glutamine synthetase in cirrhotics. Cultured hepatocytes from the two groups of rats showed a similar stimulation of urea production by addition of ammoniumacetate and/or OA to Hanks’ buffered salt solution. In Williams medium E, however, the hepatocytes from the OA group produced significantly more urea than those from controls. These results suggest that treatment of cirrhotic rats with OA considerably improves urea production favoring the detoxification of ammonia that, however, is still limited by the severe alterations in liver architecture that are not influenced by OA in a 2-wk period.

Footnotes

  • Send reprint requests to: Prof. Dr. Rolf Gebhardt, University of Tübingen, Institute of Biochemistry, Hoppe-Seyler-Str. 4, D-72076 Tübingen, Germany.

  • ↵1 This work was supported by Merz + Co. GmbH & Co., Frankfurt.

  • Abbreviations:
    ABT
    aminopyrine breath test
    ALT
    alanine animotransferase
    ALP
    alkaline phosphatase
    GlDH
    glutamate dehydrogenase
    GLUnase
    glutaminase
    GS
    glutamine synthetase
    OA
    L-Orn-L-Asp, l-ornithine-l-aspartate
    • Received January 9, 1997.
    • Accepted April 12, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 283, Issue 1
1 Oct 1997
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OtherTOXICOLOGY

Treatment of Cirrhotic Rats withl-Ornithine-l-Aspartate Enhances Urea Synthesis and Lowers Serum Ammonia Levels

Rolf Gebhardt, Gerhard Beckers, Frank Gaunitz, Wolfram Haupt, Dirk Jonitza, Sabine Klein and Ludger Scheja
Journal of Pharmacology and Experimental Therapeutics October 1, 1997, 283 (1) 1-6;

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OtherTOXICOLOGY

Treatment of Cirrhotic Rats withl-Ornithine-l-Aspartate Enhances Urea Synthesis and Lowers Serum Ammonia Levels

Rolf Gebhardt, Gerhard Beckers, Frank Gaunitz, Wolfram Haupt, Dirk Jonitza, Sabine Klein and Ludger Scheja
Journal of Pharmacology and Experimental Therapeutics October 1, 1997, 283 (1) 1-6;
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