EFFECTS OF NITRIC-OXIDE SYNTHASE INHIBITION OR SULFASALAZINE ON THE SPONTANEOUS COLITIS OBSERVED IN HLA-B27 TRANSGENIC RATS

The objective of this study was to determine the effects that certain nitric oxide synthase inhibitors have on the spontaneous intestinal an d colonic inflammation that develops in HLA-B27 transgenic rats and co mpare these data to those obtained using sulfasalazine (SZ). In an att empt to more closely mimic the clinical situation, drug treatment was begun after he onset of colitis, HLA-B27 male rats that developed clin ical signs of colitis (diarrhea/loose stools) at 17 wk of age were ran domized into fours groups consisting of one untreated colitic group an d three treatment groups that received either aminoguanidine (AG; 52 m u mol/kg/day), N-G-nitro-L-arginine methyl ester (L-NAME; 45 mu mol/kg /day) or SZ (130 mg/kg/day) in their drinking water for 14 days. Aged- matched Fisher 344 male rats were used as healthy controls. After 3 wk of treatment, ileal and colonic mucosal permeabilities, granulocyte i nfiltration and nitric oxide were quantified using blood-to-lumen clea rance of Cr-51-EDTA, tissue myeloperoxidase activity, and plasma level s of nitrate and nitrite, respectively, We found that both AG and L-NA ME but not SZ significantly attenuated the increases in plasma nitrate and nitrite levels. Interestingly, all three drugs were effective at significantly attenuating the increases in myeloperoxidase activity in the distal colon, Treatment with AG and SZ but not L-NAME were effect ive at significantly attenuating the increase in ileal and colonic per meabilities. Quantitative histological analysis revealed that AG and L -NAME but not SZ significantly attenuated the increase in the mucosal thickness and crypt depth in the distal colon compared to untreated co litis. Taken together, these data demonstrate that oral administration of certain nitric oxide synthase inhibitors or SZ to animals with act ive colitis attenuates the colonic inflammation by at least two differ ent mechanisms, One mechanism appears to be dependent on inhibition of NO production whereas the other mechanism does not.