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Site-specific lesion formation, inflammation and inducible nitric oxide synthase expression by indomethacin in the
S M Evans1, F László, B J Whittle
1Glaxo-Wellcome Research and Development, Hertfordshire, UK.
Abstract:
The involvement of nitric oxide (NO) formed by the inducible isoform of NO synthase (iNOS) has been investigated in the development of rat intestinal lesions following indomethacin administration. Over a 72-h period, indomethacin (10 mg kg(-1), s.c.) provoked a time-dependent increase in expression of iNOS (assessed by the conversion of radiolabelled L-arginine to citrulline) and enhancement of vascular leakage of radiolabelled human serum albumin in the jejunum which commenced 18 h after indomethacin. Similar effects were not observed in the ileum, colon or caecum. In addition, macroscopic lesions were detectable and myeloperoxidase activity (an index of neutrophil recruitment) were increased in the rat jejunum 18-24 h after indomethacin, but remained at basal levels in the ileum and colon. These findings suggest that indomethacin provokes a site-selective expression of iNOS in the rat jejunum which correlates with lesion formation and vascular leakage, whereas both the ileum and colon are spared.
Insights
Indomethacin induces site-selective inducible nitric oxide synthase (iNOS) expression in rat jejunum, leading to lesions and vascular leakage. Other intestinal sections remain unaffected, suggesting a protective mechanism.
Area of Science:
- Gastroenterology
- Pharmacology
- Immunology
Background:
- Indomethacin is a nonsteroidal anti-inflammatory drug known to cause gastrointestinal lesions.
- Nitric oxide (NO) plays a complex role in mucosal protection and injury.
Purpose of the Study:
- To investigate the role of inducible nitric oxide synthase (iNOS) in indomethacin-induced intestinal injury in rats.
- To determine the site-selectivity of iNOS involvement in the jejunum, ileum, colon, and caecum.
Main Methods:
- Rats were administered indomethacin subcutaneously.
- Inducible nitric oxide synthase (iNOS) expression was assessed by measuring the conversion of radiolabeled L-arginine to citrulline.
- Vascular leakage was measured using radiolabeled human serum albumin.
- Macroscopic lesions and myeloperoxidase activity (neutrophil recruitment index) were quantified.
Main Results:
- Indomethacin administration led to a time-dependent increase in iNOS expression and vascular leakage specifically in the jejunum.
- Macroscopic lesions and neutrophil recruitment were significantly elevated in the jejunum 18-24 hours post-indomethacin.
- The ileum, colon, and caecum did not exhibit these indomethacin-induced changes.
Conclusions:
- Indomethacin triggers site-selective iNOS expression in the rat jejunum, correlating with lesion development and increased vascular permeability.
- The jejunum appears particularly susceptible to indomethacin-induced injury mediated by iNOS, while other intestinal segments are spared.