Enhanced mucosal permeability and nitric oxide synthase activity in jejunum of mast cell deficient mice

Background-Recent reports have described a modulating influence of nitric oxide (NO) on intestinal mucosal permeability and have implicated a role for mast cells in this NO mediated process. Aims-To assess further the contribution of mast cells to the mucosal permeability elicited by the NO synthase inhibitor N-G-nitro-L-arginine methylester (L-NAME), using mast cell deficient (W/W-V) and mast cell replete mice (+/+). Methods-Chromium-51 EDTA clearance (from blood to jejunal lumen), jejunal NOS and myeloperoxidase (MPO) activities, and plasma nitrate/nitrite levels were monitored. Results-The increased EDTA clearance elicited by intraluminal L-NAME in W/W-V mice (4.4-fold) was significantly greater than the response observed in control (+/+) mice (1.8-fold). The exacerbated response in W/W-V mice was greatly attenuated by pretreatment with either dexamethasone (1.3-fold) or the selective inducible NOS inhibitor, aminoguanidine (1.4-fold), and partially attenuated by the mast cell stabiliser, lodoxamide (2.9-fold). Jejunal inducible NOS activity was significantly higher in W/W-V than in +/+ mice, while jejunal MPO was lower in W/W-V mice than in +/+ mice, suggesting that the higher inducible NOS in W/W-V does not result from the recruitment of inflammatory cells into the gut. The higher inducible NOS activity in the jejunum of W/W-V was significantly reduced by dexamethasone treatment. Conclusions-Our results suggest that mast cells normally serve to inhibit inducible NOS activity tonically in the gut and that inhibitors of NOS elicit a larger permeability response when this tonic inhibitory influence is released by mast cell depletion.