Suppression of adjuvant-induced arthritis by selective inhibition of inducible nitric oxide synthase.
Adjuvant-induced arthritis is a model of chronic inflammation that exhibits several pathological changes similar to those occurring in rheumatoid arthritis, an autoimmune disease in humans characterized by chronic inflammation of the joints. We have examined the role of inducible nitric oxide synthase in producing the pathological changes associated with adjuvant-induced arthritis. Plasma nitrite concentrations were maximally elevated 14 days following adjuvant administration compared to untreated control animals. Arthritic changes in the paw were first observed between days 10-12 and were maximally elevated 21 days following adjuvant administration. Inducible nitric oxide synthase immunoreactivity was found localized in the synovial tissue from adjuvant-treated rats, while untreated controls exhibited no inducible nitric oxide synthase staining. Two selective inducible nitric oxide synthase inhibitors, aminoguanidine and N-iminoethyl-L-lysine, suppressed the increase in plasma nitrite levels and joint inflammation associated with adjuvant-induced arthritis in a dose-dependent manner. N-Iminoethyl-L-lysine attenuated the inducible nitric oxide synthase immunoreactivity in adjuvant-treated rats. Blood pressure was not affected by the highest dose of N-iminoethyl-L-lysine administered in the drinking water, indicating a lack of inhibition of constitutive nitric oxide synthase.
Connor
J R
JR
Molecular Pharmacology, Inflammation Diseases Research, Searle, St. Louis, MO 63167, USA.
Manning
P T
PT
Settle
S L
SL
Moore
W M
WM
Jerome
G M
GM
Webber
R K
RK
Tjoeng
F S
FS
Currie
M G
MG
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000595:Amino Acid Sequence; D000818:Animals; D001169:Arthritis, Experimental / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D001794:Blood Pressure / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology; D007150:Immunohistochemistry; D007596:Joints / Q000378:metabolism / Q000473:pathology; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008969:Molecular Sequence Data; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase; D009573:Nitrites / Q000097:blood; D051381:Rats; D011917:Rats, Inbred Lew; D013582:Synovial Fluid / Q000201:enzymology
D006146:Guanidines; C090663:N(6)-(1-iminoethyl)lysine; D009566:Nitrates; D009573:Nitrites; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D008239:Lysine; C004479:pimagedine