ABSTRACT
Up-regulation of the inducible isoform of nitric oxide synthase (iNOS) was determined during the development of adjuvant-induced arthritis in the rat. iNOS enzymatic activity, measured in spleen tissue, appeared and increased coincidentally with the appearance and degree of paw swelling and joint destruction in this arthritis model, when measured on days 0 through 21 subsequent to inoculation of the rats with adjuvant. The increase in enzymatic activity was paralleled by an increase in the plasma nitrite/nitrate (NOx) level and the appearance of immunoreactive iNOS, as measured by Western immunoblot, in the spleens of these rats. Prophylactic administration of N-iminoethyl-L-lysine (L-NIL) completely abolished iNOS activity (plasma NOx elevation) and effectively reduced both the swelling and radiographic changes in the joint tissues of the noninjected paw measured on day 21. However, therapeutic administration of L-NIL beginning on day 14 had no effect on the inflammatory or arthritic changes measured on day 21, even though plasma NOx levels were reduced to that of the naive controls. These results suggest that iNOS may be involved with the initial stages of the immune response to adjuvant injection, but its product, NO, does not mediate the chronic inflammation and joint destruction which occur during the later phase in this model.
Subject(s)
Arthritis, Experimental/pathology , Enzyme Inhibitors/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , Animals , Arthritis, Experimental/prevention & control , Body Weight/drug effects , Female , Inflammation/pathology , Lysine/analogs & derivatives , Lysine/pharmacology , Nitric Oxide Synthase/metabolism , Nitric Oxide Synthase Type II , Organ Size/drug effects , Rats , Rats, Inbred Lew , Up-Regulation/drug effectsABSTRACT
Investigation of furans, pyrroles and pyrazolones identified 3-pyridyl-2,5-diaryl-pyrroles as potent, orally bioavailable inhibitors of p38 kinase. 3-(4-pyridyl-2-(4-fluoro-phenyl)-5-(4-methylsulfinylphenyl)-pyrrol e (L-167307) reduces secondary paw swelling in the rat adjuvant arthritis model: ID50 = 7.4 mg/kg/b.i.d.
Subject(s)
Calcium-Calmodulin-Dependent Protein Kinases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Furans/pharmacology , Mitogen-Activated Protein Kinases , Pyrazoles/pharmacology , Pyrroles/pharmacology , Animals , Arthritis, Experimental/drug therapy , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Furans/chemical synthesis , Furans/pharmacokinetics , Humans , Pyrazoles/chemical synthesis , Pyrazoles/pharmacokinetics , Pyrroles/chemical synthesis , Pyrroles/pharmacokinetics , Rats , p38 Mitogen-Activated Protein KinasesABSTRACT
Adult males and females of three strains of mice, C57BL/10J, C57BL/6J and DBA/2J, were intubated or injected intraperitoneally with 0.02 ml/g body weight of a 25% alcohol solution. Thirty minutes later, their blood alcohol levels (BAL) were measured. Another group of mice, including both sexes, representative of the three strains, was fasted for 12 h and sacrificed; their stomachs were removed, homogenized, and assayed for gastric alcohol dehydrogenase (GAD) activity. Higher BALs were found in all intubated females compared to the intubated males. The reverse was observed in the injected group, which showed the males with the highest BAL values. GAD activity was evidenced in both sexes of the three strains and it was highest in the males. Strain-related differences were evident in the intubated groups and not in the injected groups. Intubated DBA animals had the lowest BALs as well as the highest GAD values. The results provide evidence for first-pass alcohol metabolism in mice and show the effects of sex and strain on gastric oxidation of alcohol.
