Amelioration of chronic ileitis by nitric oxide synthase inhibition

Nitric oxide synthesis appears to be elevated in inflammatory bowel disease, but little is known about the contribution of nitric oxide to the pathophysiological process. To address this issue, we included the nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) in the drinking water (10 or 100 micrograms/ml) of guinea pigs immediately after induction of ileitis by intraluminal trinitrobenzenesulfonic acid (TNBS 30 mg/kg in 50% ethanol). Guinea pigs were sacrificed after 7 days of this ad libitum treatment. Control groups received either intraluminal TNBS, saline or ethanol (TNBS vehicle) without L-NAME or TNBS + D-NAME (100 micrograms/ml), the inactive enantiomer. Immediately before sacrifice, guinea pigs were anesthetized and saline was administered intraluminally at the site of TNBS or saline administration and then withdrawn after 30 min. Change in lavage volume and lavage protein and nitrite levels were measured, as well as tissue myeloperoxidase and bowel wall thickness (weight/length). TNBS administration resulted in an increase in tissue thickness, myeloperoxidase and lavage protein and nitrite levels over sham controls. Oral L-NAME prevented these responses. D-NAME was ineffective with the exception of tissue thickness. The change in intestinal lavage fluid volume indicated that reabsorptive processes dominated in the sham and TNBS + L-NAME groups, and secretory responses predominated in TNBS and TNBS + D-NAME animals. In contrast to TNBS-induced ileitis, L-NAME (100 micrograms/ml, p.o., 7 days) administration to intact animals resulted in a local inflammatory response (i.e., increased myeloperoxidase activity and a fluid secretory response).(ABSTRACT TRUNCATED AT 250 WORDS)