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Induction of nitric oxide synthase and microvascular injury in the rat jejunum provoked by indomethacin
Author(s) -
Whittle Brendan J.R.,
László Ferenc,
Evans Steven M.,
Moncada Salvador
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb15066.x
Subject(s) - nitric oxide synthase , chemistry , nitric oxide , endocrinology , medicine , jejunum , pharmacology , indometacin , enzyme inhibitor , biochemistry , in vitro , prostaglandin endoperoxide synthase
1 The role of nitric oxide (NO) formed by the inducible isoform of NO synthase (NOS) in the generation of indomethacin‐induced intestinal microvascular leakage was investigated in the rat. 2 Indomethacin (10 mg kg −1 , s.c.) provoked an elevation of vascular leakage of radiolabelled human serum albumin in the jejunum over 48 h, commencing 18 h after its administration. This was associated with the induction of a calcium‐independent NOS, as assessed by the conversion of radiolabelled L‐arginine to citrulline. 3 Pretreatment with the glucocorticoid, dexamethasone (1 mg kg −1 day −1 , s.c.) inhibited the induction of NOS and reduced jejunal microvascular leakage, determined 24 and 48 h after indomethacin. 4 Administration of the broad‐spectrum antibiotic, ampicillin (800 mg kg −1 day −1 , p.o.) likewise inhibited both the induction of NOS and the plasma leakage observed 24 and 48 h after indomethacin. 5 Ampicillin pretreatment did not, however, inhibit the induction of NOS, determined 5 h following endotoxin (3 mg kg −1 i.v.) challenge. Furthermore, incubation with ampicillin (1 mM, 10 min) did not inhibit the activity of the calcium‐independent isoform in vitro . 6 Administration of the NOS inhibitor, N G ‐nitro‐L‐arginine methyl ester (L‐NAME, 2–10 mg kg −1 , s.c.), at the time of the detectable expression of the inducible NOS (18 h after indomethacin), dose‐dependently attenuated the plasma leakage, determined 6 later. This effect was reversed by pretreatment with L‐arginine (300 mg kg −1 , s.c.) 15 min before L‐NAME. 7 These findings suggest that induction of a calcium‐independent NOS following indomethacin administration involves gut bacteria and leads to microvascular injury in the rat jejunum.