Comparison of the nitric oxide synthase inhibitors methylarginine and aminoguanidine as prophylactic and therapeutic agents in rat adjuvant arthritis

M. Stefanovic-Racic, K. Meyers, C. Meschter, J. W. Coffey, R. A. Hoffman, Christopher H Evans

Research output: Contribution to journalArticle

105 Citations (Scopus)

Abstract

Objective. To compare the nitric oxide synthase (NOS) inhibitors NG-methyl-L-arginine (L-NMA) and aminoguanidine (AG) as prophylactic and therapeutic agents in rat adjuvant induced arthritis (AIA). Methods. Arthritis was induced in male Lewis rats by the injection of adjuvant into the base of the tail. L-NMA or AG was administered twice daily by gastric intubation starting at the time: of adjuvant injection, just before the onset of clinical symptoms, or after the onset of clinical symptoms. Paw swelling, plasma fibrinogen levels and urinary NO2-/NO3- excretion were measured to assess the effect of the inhibitors on the arthritis response and whole body NO biosynthesis. Selected were also evaluated histopathologically. The abilities of L-NMA, AG and another NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), to inhibit NO production by chondrocytes and synoviocytes were also compared. Results. Treatment with L-NMA (400 mg/kg/day) or AG (500 mg/kg/day) reduced the urinary excretion of NO2-/NO3- to the control level. L-NMA suppressed the development of AIA when administered prophylactically; however, its antiarthritic properties declined with increasing delay of application. It was only weakly effective against established AIA. AG had neither a prophylactic nor a therapeutic antiarthritic effect. AG and L-NAME were much weaker inhibitors of NO production by chondrocytes and synoviocytes than L-NMA. Conclusion. Although L-NMA completely suppresses the development of AIA when administered prophylactically, it is much less effective when administered therapeutically. Furthermore, not all inhibitors of NOS show equal prophylactic activity against AIA. In addition, NOS inhibitors may be only weakly therapeutic, or even detrimental, in established disease. These findings should be considered when evaluating NOS inhibitors as potential therapeutic agents for the treatment of established human arthritis.

Original languageEnglish (US)
Pages (from-to)1922-1928
Number of pages7
JournalJournal of Rheumatology
Volume22
Issue number10
StatePublished - 1995
Externally publishedYes

Fingerprint

Experimental Arthritis
Nitric Oxide Synthase
NG-Nitroarginine Methyl Ester
Arthritis
Chondrocytes
Therapeutics
Injections
Therapeutic Uses
Intubation
Fibrinogen
Arginine
pimagedine
Tail
Stomach

Keywords

  • Arthritis
  • Cartilage
  • Inflammation
  • Nitric oxide
  • Synovium

ASJC Scopus subject areas

  • Immunology
  • Rheumatology

Cite this

Comparison of the nitric oxide synthase inhibitors methylarginine and aminoguanidine as prophylactic and therapeutic agents in rat adjuvant arthritis. / Stefanovic-Racic, M.; Meyers, K.; Meschter, C.; Coffey, J. W.; Hoffman, R. A.; Evans, Christopher H.

In: Journal of Rheumatology, Vol. 22, No. 10, 1995, p. 1922-1928.

Research output: Contribution to journalArticle

Stefanovic-Racic, M. ; Meyers, K. ; Meschter, C. ; Coffey, J. W. ; Hoffman, R. A. ; Evans, Christopher H. / Comparison of the nitric oxide synthase inhibitors methylarginine and aminoguanidine as prophylactic and therapeutic agents in rat adjuvant arthritis. In: Journal of Rheumatology. 1995 ; Vol. 22, No. 10. pp. 1922-1928.
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abstract = "Objective. To compare the nitric oxide synthase (NOS) inhibitors NG-methyl-L-arginine (L-NMA) and aminoguanidine (AG) as prophylactic and therapeutic agents in rat adjuvant induced arthritis (AIA). Methods. Arthritis was induced in male Lewis rats by the injection of adjuvant into the base of the tail. L-NMA or AG was administered twice daily by gastric intubation starting at the time: of adjuvant injection, just before the onset of clinical symptoms, or after the onset of clinical symptoms. Paw swelling, plasma fibrinogen levels and urinary NO2-/NO3- excretion were measured to assess the effect of the inhibitors on the arthritis response and whole body NO biosynthesis. Selected were also evaluated histopathologically. The abilities of L-NMA, AG and another NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), to inhibit NO production by chondrocytes and synoviocytes were also compared. Results. Treatment with L-NMA (400 mg/kg/day) or AG (500 mg/kg/day) reduced the urinary excretion of NO2-/NO3- to the control level. L-NMA suppressed the development of AIA when administered prophylactically; however, its antiarthritic properties declined with increasing delay of application. It was only weakly effective against established AIA. AG had neither a prophylactic nor a therapeutic antiarthritic effect. AG and L-NAME were much weaker inhibitors of NO production by chondrocytes and synoviocytes than L-NMA. Conclusion. Although L-NMA completely suppresses the development of AIA when administered prophylactically, it is much less effective when administered therapeutically. Furthermore, not all inhibitors of NOS show equal prophylactic activity against AIA. In addition, NOS inhibitors may be only weakly therapeutic, or even detrimental, in established disease. These findings should be considered when evaluating NOS inhibitors as potential therapeutic agents for the treatment of established human arthritis.",
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T1 - Comparison of the nitric oxide synthase inhibitors methylarginine and aminoguanidine as prophylactic and therapeutic agents in rat adjuvant arthritis

AU - Stefanovic-Racic, M.

AU - Meyers, K.

AU - Meschter, C.

AU - Coffey, J. W.

AU - Hoffman, R. A.

AU - Evans, Christopher H

PY - 1995

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N2 - Objective. To compare the nitric oxide synthase (NOS) inhibitors NG-methyl-L-arginine (L-NMA) and aminoguanidine (AG) as prophylactic and therapeutic agents in rat adjuvant induced arthritis (AIA). Methods. Arthritis was induced in male Lewis rats by the injection of adjuvant into the base of the tail. L-NMA or AG was administered twice daily by gastric intubation starting at the time: of adjuvant injection, just before the onset of clinical symptoms, or after the onset of clinical symptoms. Paw swelling, plasma fibrinogen levels and urinary NO2-/NO3- excretion were measured to assess the effect of the inhibitors on the arthritis response and whole body NO biosynthesis. Selected were also evaluated histopathologically. The abilities of L-NMA, AG and another NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), to inhibit NO production by chondrocytes and synoviocytes were also compared. Results. Treatment with L-NMA (400 mg/kg/day) or AG (500 mg/kg/day) reduced the urinary excretion of NO2-/NO3- to the control level. L-NMA suppressed the development of AIA when administered prophylactically; however, its antiarthritic properties declined with increasing delay of application. It was only weakly effective against established AIA. AG had neither a prophylactic nor a therapeutic antiarthritic effect. AG and L-NAME were much weaker inhibitors of NO production by chondrocytes and synoviocytes than L-NMA. Conclusion. Although L-NMA completely suppresses the development of AIA when administered prophylactically, it is much less effective when administered therapeutically. Furthermore, not all inhibitors of NOS show equal prophylactic activity against AIA. In addition, NOS inhibitors may be only weakly therapeutic, or even detrimental, in established disease. These findings should be considered when evaluating NOS inhibitors as potential therapeutic agents for the treatment of established human arthritis.

AB - Objective. To compare the nitric oxide synthase (NOS) inhibitors NG-methyl-L-arginine (L-NMA) and aminoguanidine (AG) as prophylactic and therapeutic agents in rat adjuvant induced arthritis (AIA). Methods. Arthritis was induced in male Lewis rats by the injection of adjuvant into the base of the tail. L-NMA or AG was administered twice daily by gastric intubation starting at the time: of adjuvant injection, just before the onset of clinical symptoms, or after the onset of clinical symptoms. Paw swelling, plasma fibrinogen levels and urinary NO2-/NO3- excretion were measured to assess the effect of the inhibitors on the arthritis response and whole body NO biosynthesis. Selected were also evaluated histopathologically. The abilities of L-NMA, AG and another NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), to inhibit NO production by chondrocytes and synoviocytes were also compared. Results. Treatment with L-NMA (400 mg/kg/day) or AG (500 mg/kg/day) reduced the urinary excretion of NO2-/NO3- to the control level. L-NMA suppressed the development of AIA when administered prophylactically; however, its antiarthritic properties declined with increasing delay of application. It was only weakly effective against established AIA. AG had neither a prophylactic nor a therapeutic antiarthritic effect. AG and L-NAME were much weaker inhibitors of NO production by chondrocytes and synoviocytes than L-NMA. Conclusion. Although L-NMA completely suppresses the development of AIA when administered prophylactically, it is much less effective when administered therapeutically. Furthermore, not all inhibitors of NOS show equal prophylactic activity against AIA. In addition, NOS inhibitors may be only weakly therapeutic, or even detrimental, in established disease. These findings should be considered when evaluating NOS inhibitors as potential therapeutic agents for the treatment of established human arthritis.

KW - Arthritis

KW - Cartilage

KW - Inflammation

KW - Nitric oxide

KW - Synovium

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