Role of nitric oxide in the circulatory failure and organ injury in a rodent 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 aureus, namely lipoteichoic acid (LTA) and peptidoglycan (PepG). This is associated with the expression of the inducible isoform of nitric oxide synthase (iNOS) in various organs. We have investigated the effects of dexamethasone (which prevents the expression of iNOS protein) or aminoguanidine (an inhibitor of iNOS activity) on haemodynamics, multiple organ dysfunction syndrome (MODS) as well as iNOS activity elicited by LTA + PepG in anaesthetized rats. 2. Co-administration of LTA (3 mg kg-1, i.v.) and PepG (10 mg kg-1, i.v.) resulted in a significant increase in the plasma levels of tumour necrosis factor-alpha (TNF alpha, maximum at 90 min) as well as a biphasic fall in mean arterial blood pressure (MAP) from 120 +/- 3 mmHg (time 0) to 77 +/- 5 mmHg (at 6 h, n = 8; P < 0.05). This hypotension was associated with a significant tachycardia (4-6 h, P < 0.05) and a reduction of the pressor response elicited by noradrenaline (NA, 1 microgram kg-1, i.v., at 1-6 h; n = 8, P < 0.05). Furthermore, LTA + PepG caused time-dependent increases in the serum levels of markers of hepatocellular injury, glutamate-pyruvate-transminase (GPT) and glutamate-oxalacetate-transaminase (GOT). In addition, urea and creatinine (indicators of renal dysfunction) were increased. There was also a fall in arterial oxygen tension (PaO2), indicating respiratory dysfunction, and metabolic acidosis as shown by the significant drop in pH, PaCO2 and HCO3-. These effects caused by LTA + PepG were associated with the induction of iNOS activity in aorta, liver, kidney and lungs as well as increases in serum levels of nitrite+nitrate (total nitrite). 3. Pretreatment of rats with dexamethasone (3 mg kg-1, i.p.) at 120 min before LTA + PepG administration significantly attenuated these adverse effects as well as the increases in the plasma levels of TNF alpha caused by LTA + PepG. The protective effects of dexamethasone were associated with a prevention of the increase in iNOS activity (in aorta, liver, lung, kidney), the expression of iNOS protein (in lungs), as well as in the increase in the plasma levels of total nitrite. 4. Treatment of rats with aminoguanidine (5 mg kg-1 + 10 mg kg-1 h-1) starting at 120 min after LTA + PepG attenuated most of the adverse effects and gave a significant inhibition of iNOS activity (in various organs) as well as an inhibition of the increase in total plasma nitrite. However, aminoguanidine did not improve renal function although this agent caused a substantial inhibition of NOS activity in the kidney. 5. Thus, an enhanced formation of NO by iNOS importantly contributes to the circulatory failure, hepatocellular injury, respiratory dysfunction and the metabolic acidosis, but not the renal failure, caused by LTA + PepG in the anaesthetized rat.
Kengatharan
K M
KM
William Harvey Research Institute, St Bartholomew's Hospital Medical College, London.
De Kimpe
S J
SJ
Thiemermann
C
C
D000136:Acid-Base Equilibrium / Q000187:drug effects; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D015153:Blotting, Western; D003907:Dexamethasone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D006439:Hemodynamics / Q000502:physiology; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D009569:Nitric Oxide / Q000097:blood / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010457:Peptidoglycan / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic / Q000473:pathology / Q000503:physiopathology*; D013211:Staphylococcus aureus / Q000378:metabolism*; D013682:Teichoic Acids / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D006146:Guanidines; D008070:Lipopolysaccharides; D010457:Peptidoglycan; D013682:Teichoic Acids; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C009900:lipoteichoic acid; D003907:Dexamethasone; D019001:Nitric Oxide Synthase; C004479:pimagedine