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


CONCLUSIONS
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.
Stefanovic-Racic
M
M
Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, PA 15261, USA.
Meyers
K
K
Meschter
C
C
Coffey
J W
JW
Hoffman
R A
RA
Evans
C H
CH
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D002358:Cartilage, Articular / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000627:therapeutic use*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D011817:Rabbits; D051381:Rats; D011917:Rats, Inbred Lew; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism; D019323:omega-N-Methylarginine / Q000627:therapeutic use*
D006146:Guanidines; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester