Interactions of constitutive nitric oxide with PAF and thromboxane on rat intestinal vascular integrity in acute endotoxaemia.
1. The involvement of endogenous platelet activating factor (PAF) and thromboxane A2 in the acute microvascular damage in the ileum and colon induced by the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) following endotoxin administration was investigated in the rat over a 1 h period. 2. Administration of L-NAME (1-10 mg kg-1, s.c.) concurrently with E. coli lipopolysaccharide (LPS; 3 mg kg-1, i.v.) dose-dependently increased vascular permeability in the ileum and colon, as determined by the leakage of radiolabelled albumin, and caused macroscopic mucosal damage in the ileum determined 1 h later. Neither LPS administration nor L-NAME (5 mg kg-1) alone affected resting vascular permeability. 3. Infusion of phenylephrine (10 micrograms kg-1 min-1, i.v. for 1 h) caused an elevation in blood pressure similar to that found following L-NAME administration (5 mg kg-1, i.v. or s.c.), but did not increase intestinal vascular permeability, when administered with LPS (3 mg kg-1, i.v.). 4. The increased vascular permeability in the ileum and colon and macroscopic damage in the ileum, induced by L-NAME (5 mg kg-1, s.c.) and LPS (3 mg kg-1, i.v.) was dose-dependently inhibited following s.c. pretreatment (15 min before challenge) with the thromboxane synthase inhibitors, OKY 1581 (5-25 mg kg-1) or 1-benzyl-imidazole (1-50 mg kg-1), or with the thromboxane receptor antagonist, BM 13177 (0.2-2 mg kg-1). 5. Pretreatment with the cyclo-oxygenase inhibitor, indomethacin (2-5 mg kg-', s.c., 15 min before challenge) reduced the microvascular injury in the ileum and colon and macroscopic lesions in the ileum,observed after the concurrent administration of L-NAME and LPS.6. Pretreatment (15 min) with the PAF-receptor antagonists, WEB 2086 (0.5-1 mg kg-', s.c.) or BN52021 (2.5-10 mg kg-', s.c.) likewise attenuated this intestinal vascular injury.7. Combined administration of low doses of l-benzyl-imidazole (1 mg kg-') with WEB 2086(0.5 mg kg-')15 min before L-NAME and LPS challenge, abolished this vascular damage and macroscopic injury.8. These results suggest that PAF and thromboxane A2 are released acutely following challenge with a low dose of endotoxin. However, these mediators do not appear to injure the intestinal micro vascular bed unless NO synthase is concurrently inhibited. Such findings support the protective role of constitutively-formed NO, counteracting the injurious vascular actions of cytotoxic mediators released under pathological conditions.
László
F
F
Department of Pharmacology, Wellcome Research Laboratories, Beckenham, Kent.
Whittle
B J
BJ
Moncada
S
S
D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002196:Capillaries / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004224:Diterpenes; D004926:Escherichia coli; D046934:Ginkgolides; D007413:Intestinal Mucosa / Q000473:pathology; D007422:Intestines / Q000098:blood supply* / Q000502:physiology; D007783:Lactones / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D010656:Phenylephrine / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors; D013928:Thromboxane A2 / Q000502:physiology*; D014230:Triazoles / Q000494:pharmacology
D001381:Azepines; D016861:Cyclooxygenase Inhibitors; D004224:Diterpenes; D046934:Ginkgolides; D007783:Lactones; D008070:Lipopolysaccharides; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D017482:Receptors, Thromboxane; D014230:Triazoles; C039351:platelet activating factor receptor; C052518:WEB 2086; D010656:Phenylephrine; D009569:Nitric Oxide; D013928:Thromboxane A2; C045856:ginkgolide B