title: Delayed circulatory failure due to the induction of nitric oxide synthase by lipoteichoic acid from Staphylococcus aureus in anaesthetized rats.
abstract: 1. This study investigates the effect of lipoteichoic acid (LTA) from the cell wall of Staphylococcus aureus, a micro-organism without endotoxin, on haemodynamics and induction of nitric oxide synthase (iNOS) in the anaesthetized rat. 2. Intravenous injection of LTA (10 mg kg-1) resulted in a decrease in blood pressure from 123 +/- 1 mmHg to 83 +/- 7 mmHg after 270 min (P < 0.001) and a reduction of the pressor response to noradrenaline (1 microgram kg-1) from 33 +/- 1 mmHg.min to 23 +/- 3 mmHg.min after 270 min (P < 0.05). 3. The delayed circulatory failure (hypotension and vascular hyporeactivity) caused by LTA was prevented by pretreatment of rats with dexamethasone (10 mg kg-1, 60 min prior to LTA) or the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA, 10 mg kg-1 h-1, i.v. infusion starting 30 min prior to LTA). 4. In contrast, treatment of rats with polymyxin B (0.05 mg kg-1), an agent which binds endotoxin (lipopolysaccharides, LPS), did not affect the delayed circulatory failure caused by LTA. Polymyxin B, however, attenuated the hypotension and vascular hyporeactivity to noradrenaline afforded by endotoxaemia (2 mg kg-1 LPS, i.v.) for 270 min. 5. The delayed circulatory failure caused by LTA was associated with a time-dependent increase in (i) the expression of iNOS protein in the lung (Western blot analysis), and (ii) iNOS activity. This increase in iNOS protein and activity was prevented by pretreatment of LTA-rats with dexamethasone (10 mg kg-1). 6. Intravenous injection of LTA resulted in an increase in serum tumour necrosis factor (TNF)-alpha(maximum at 90 min after LTA), which was attenuated by pretreatment of rats with dexamethasone(10 mg kg-1, 60 min prior to LTA). The magnitude of the rise in TNF-alpha caused by LTA was similar to the one elicited by LPS (10mgkg-', i.v.).7. Thus, an enhanced formation of nitric oxide following the induction of iNOS contributes importantly to the delayed vascular failure (hypotension and vascular hyporeactivity) caused by LTA in the anaesthetized rat. We suggest that the endogenous release of TNF-alpha contributes to the induction ofiNOS caused by LTA in vivo.
authors.affiliation: William Harvey Research Institute, St. Bartholomew's Hospital Medical College, London.
authors.forename: S J
authors.initials: SJ
authors.lastname: De Kimpe
authors.forename: M L
authors.initials: ML
authors.lastname: Hunter
authors.forename: C E
authors.initials: CE
authors.lastname: Bryant
authors.forename: C
authors.initials: C
authors.lastname: Thiemermann
authors.forename: J R
authors.initials: JR
authors.lastname: Vane
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis*; D000777:Anesthetics; D000818:Animals; D002303:Cardiac Output, Low / Q000139:chemically induced* / Q000201:enzymology; D004790:Enzyme Induction / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D019001:Nitric Oxide Synthase; D051381:Rats; D017208:Rats, Wistar; D012770:Shock, Cardiogenic / Q000139:chemically induced; D013211:Staphylococcus aureus / Q000737:chemistry*; D013682:Teichoic Acids / Q000494:pharmacology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000777:Anesthetics; D008070:Lipopolysaccharides; D013682:Teichoic Acids; D014409:Tumor Necrosis Factor-alpha; C009900:lipoteichoic acid; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases