Gastric and thymic assay of acute oral treatment of rats with nitric oxide esters of ibuprofen or indomethacin.
Two common non-steroidal anti-inflammatory drugs (NSAIDs) and their nitric oxide (NO) adducts were evaluated for effects on stomach and thymus. Following 4-h duration (acute) oral dosing of fasted male Wistar rats, 1.33 x 10(-4)mol/kg of ibuprofen caused significant visual irritation score and microscopic thinning, although an ulceration assay proved insensitive. Ibuprofen esterified with NO abolished irritation and significantly reduced thinning. Gastro-protective effects of NO-linked ibuprofen were associated with higher levels of diaphorase by optical density, an enzymatic marker of local synthesis of nitric oxide. Both indomethacin and its congener at 2 x 10(-5)mol/kg produced microscopic signs of thinning only, not visible irritation or alteration of diaphorase staining. Results suggest that NO-linked ibuprofen can promote resistance to mucosal injury, possibly via local synthesis of NO. All NO-congeners and parent NSAIDs produced comparable reductions in the abundance of medullary nitrergic cells, those synthesising NO in thymus, without significantly lowering T-cellularity, the relative size of cortex wherein T-cells are produced. Findings indicate disturbance of T-cell tolerance, consistent with increased risk of autoimmune susceptibility.
Downing
James E G
JE
School of Pharmacy and Chemistry, Liverpool John Moores University, Byrom St., Liverpool L3 3AF, UK. jdowning@livjm.ac.uk
Madden
Judith C
JC
Ingram
Matthew J
MJ
Rostron
Christopher
C
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000633:toxicity; D004951:Esterification; D005753:Gastric Mucosa / Q000187:drug effects; D007052:Ibuprofen / Q000737:chemistry / Q000633:toxicity*; D007213:Indomethacin / Q000737:chemistry / Q000633:toxicity*; D008297:Male; D009569:Nitric Oxide / Q000008:administration & dosage* / Q000737:chemistry; D010437:Peptic Ulcer / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D051381:Rats; D017208:Rats, Wistar; D013270:Stomach / Q000187:drug effects* / Q000473:pathology*; D013950:Thymus Gland / Q000187:drug effects* / Q000473:pathology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D009569:Nitric Oxide; D007052:Ibuprofen; D007213:Indomethacin