DELAYED CIRCULATORY FAILURE DUE TO THE INDUCTION OF NITRIC-OXIDE SYNTHASE BY LIPOTEICHOIC ACID FROM STAPHYLOCOCCUS-AUREUS IN ANESTHETIZED RATS

1 This study investigates the effect of lipoteichoic acid (LTA) from t he cell wall of Staphylococcus aureus, a micro-organism without endoto xin, 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 presser respons e to noradrenaline (1 mu g kg(-1)) from 33 +/- 1 mmHg.min to 23 +/- 3 mmHg.min after 270 min (P<0.05). 3 The delayed circulatory failure (hy potension 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 af fect the delayed circulatory failure caused by LTA. Polymyxin B, howev er, attenuated the hypotension and vascular hyporeactivity to noradren aline 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 ti me-dependent increase in (i) the expression of iNOS protein in the lun g (Western blot analysis), and (ii) iNOS activity. This increase in iN OS 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 th e rise in TNF-alpha caused by LTA was similar to the one elicited by L PS (10 mg kg(-1), i.v.). 7 Thus, an enhanced formation of nitric oxide following the induction of iNOS contributes importantly to the delaye d 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 of iNOS caused by LTA in viv o.