INHIBITION OF CALCIUM-DEPENDENT NITRIC-OXIDE SYNTHASE CAUSES ILEITIS AND LEUKOCYTOSIS IN GUINEA-PIGS

As nitric oxide reduces gut epithelial permeability, we designed a stu dy to determine if chronic nitric oxide synthase inhibition predispose s the gut to inflammation. Nitric oxide synthase (NOS) inhibitors were administered in the drinking water ad libitum, for seven days: aminog uanidine (10 mu g/ml), a selective inhibitor of the inducible form of nitric oxide synthase; and N-G-nitro-L-arginine methyl ester (L-NAME, 1, 10, and 100 mu g/ml), which inhibits both the constitutive and indu cible forms. Control animals drank tap water only or water with D-NAME , the inactive enantiomer. After one week, circulating leukocyte count and tissue myeloperoxidase activity were measured. L-NAME (100 mu g/m l) but not D-NAME or aminoguanidine, caused a twofold increase in a ci rculating leukocyte numbers. This increase in leukocyte numbers was ti me- and dose-dependent but the differential count was unaltered. Tissu e myeloperoxidase (MPO) activity as an index of granulocyte infiltrati on was comparable in all groups in the stomach, jejunum, colon, liver, lung, kidney, heart, and skeletal muscle. However, ileal MPO activity was elevated threefold in the L-NAME- (100 mu g/ml) treated group (P < 0.05). Results in the D-NAME and aminoguanidine groups were similar to controls. L-NAME administration resulted in a reduction in NOS acti vity ([C-14]citrulline formation) in the ileum but not jejunum, wherea s cGMP levels were elevated in both ileum and jejunum. We conclude tha t chronic inhibition of the constitutive form of nitric oxide synthase predisposes the ileum to inflammation and leads to a progressive leuk ocytosis.