Abstract

The objective of this study was to determine the effects that certain nitric oxide synthase inhibitors have on the spontaneous intestinal and colonic inflammation that develops in HLA-B27 transgenic rats and compare these data to those obtained using sulfasalazine (SZ). In an attempt to more closely mimic the clinical situation, drug treatment was begun after the onset of colitis. HLA-B27 male rats that developed clinical signs of colitis (diarrhea/loose stools) at 17 wk of age were randomized into fours groups consisting of one untreated colitic group and three treatment groups that received either aminoguanidine (AG; 52 μmol/kg/day), N^G-nitro-l-arginine methyl ester (L-NAME; 45 μmol/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 infiltration and nitric oxide were quantified using blood-to-lumen clearance of ⁵¹Cr-EDTA, tissue myeloperoxidase activity, and plasma levels of nitrate and nitrite, respectively. We found that both AG and L-NAME 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 effective at significantly attenuating the increase in ileal and colonic permeabilities. 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 colitis. Taken together, these data demonstrate that oral administration of certain nitric oxide synthase inhibitors or SZ to animals with active colitis attenuates the colonic inflammation by at least two different mechanisms. One mechanism appears to be dependent on inhibition of NO production whereas the other mechanism does not.