ROLE OF NITRIC-OXIDE IN THE CIRCULATORY FAILURE AND ORGAN INJURY IN ARODENT MODEL OF GRAM-POSITIVE SHOCK

1 The pathological features of Gram-positive shock can be mimicked by the co-administration of two cell wall components of Staphylococcus au reus, namely lipoteichoic acid (LTA) and peptidoglycan (PepG). This is associated with the expression of the inducible isoform of nitric oxi de synthase (iNOS) in various organs. We have investigated the effects of dexamethasone (which prevents the expression of iNOS protein) or a minoguanidine (an inhibitor of iNOS activity) on haemodynamics, multip le organ dysfunction syndrome (MODS) as well as iNOS activity elicited by LTA+PepG in anaesthetized rats. 2 Co-administration of LTA (3mg kg (-1), i.v.) and PepG (10 mg kg(-1), i.v.) resulted in a significant in crease in the plasma levels of tumour necrosis factor-alpha (TNFalpha, maximum at 90 min) as welll as a biphasic fall in mean arterial blood pressure (MAP) from 120plusminus3 mmHg (time 0) to 77plusminus5 mmHg (at 6 h,n=8; P less than 0.05). This hypotension was associated with a significant tachycardia (4-6 h, P less than 0.05) and a reduction of the pressor response elicited by noradrenaline (NA, 1 mu g kg(-1), i.v ., at 1-6 h; n=8, P less than 0.05). Furthermore, LTA+PepG caused time -dependent increases in the serum levels of markers of hepatocellular injury, glutamate-pyruvate-transaminase (GPT) and glutamate-oxalacetat e-transaminase (GOT). In addition, urea and creatinine (indicators of renal dysfunction) were increased. There was also a fall in arterial o xygen tension (PaO2), indicating respiratory dysfunction, and metaboli c acidosis as shown by the significant drop in pH, PaCO2 and HCO3-. Th ese effects caused by LTA+PepG were associated with the induction of i NOS activity in aorta, liver, kidney and lungs as well as increases in serum levels of nitrite+nitrite (total nitrite). 3 Pretreatment of ra ts with dexamethasone (3 mg kg(-1), i.p.) at 120 min before LTA+PepG a dministration significantly attenuated these adverse effects as well a s the increases in the plasma levels of TNFalpha caused by LTA+PepG. T he protective effects of dexamethasone were associated with a preventi n of the increase in iNOS activity (in aorta, liver, lung, kidney), th e expression of iNOS protein (in lungs), as well as in the increase in the plasma levels of total nitrite. 4 Treatment of rats with aminogua nidine (5 mg kg(-1) + 10 mg kg(-1) h(-1)) starting at 120 min after LT A+PepG attenuated most of the adverse effects and gave a significant i nhibition of iNOS activity (in various organs) as well as an inhibitio n of the increase in total plasma nitrite. However, aminoguanidine did not improve renal function although this agent caused a substantial i nhibition of NOS activity in the kidney. 5 Thus, an enhanced formation of NO by iNOS importantly contributes to the circulatory failure, hep atocellular injury, respiratory dysfunction and the metabolic acidosis , but not the renal failure, caused by LTA+PepG in the anaesthetized r at.