Inhibition of calcium-dependent nitric oxide synthase causes ileitis and leukocytosis in guinea pigs.
As nitric oxide reduces gut epithelial permeability, we designed a study to determine if chronic nitric oxide synthase inhibition predisposes the gut to inflammation. Nitric oxide synthase (NOS) inhibitors were administered in the drinking water ad libitum, for seven days: aminoguanidine (10 micrograms/ml), a selective inhibitor of the inducible form of nitric oxide synthase; and NG-nitro-L-arginine methyl ester (L-NAME, 1, 10, and 100 micrograms/ml), which inhibits both the constitutive and inducible 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 micrograms/ml), but not D-NAME or aminoguanidine, caused a twofold increase in a circulating leukocyte numbers. This increase in leukocyte numbers was time- and dose-dependent, but the differential count was unaltered. Tissue myeloperoxidase (MPO) activity as an index of granulocyte infiltration 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 micrograms/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 activity ([14C]citrulline formation) in the ileum but not jejunum, whereas cGMP levels were elevated in both ileum and jejunum. We conclude that chronic inhibition of the constitutive form of nitric oxide synthase predisposes the ileum to inflammation and leads to a progressive leukocytosis.
Miller
M J
MJ
Department of Pediatrics, Louisiana State University School of Medicine, New Orleans 70112.
Munshi
U K
UK
Sadowska-Krowicka
H
H
Kakkis
J L
JL
Zhang
X J
XJ
Eloby-Childress
S
S
Clark
D A
DA
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002956:Citrulline / Q000096:biosynthesis; D006152:Cyclic GMP / Q000032:analysis; D005260:Female; D006146:Guanidines / Q000494:pharmacology; D006168:Guinea Pigs; D007079:Ileitis / Q000139:chemically induced*; D007958:Leukocyte Count; D007964:Leukocytosis / Q000139:chemically induced*; D019331:NG-Nitroarginine Methyl Ester; D019001:Nitric Oxide Synthase; D009195:Peroxidase / Q000032:analysis
D006146:Guanidines; D002956:Citrulline; D001120:Arginine; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D006152:Cyclic GMP; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester