Search

We investigated nitric oxide (NO) as a possible cause of the cardiac dysfunction associated with high, lethal doses of tumor necrosis factor-alpha (TNF-alpha) in dogs. Eighty-seven awake, 2-year-old (10-12 kg), purpose-bred beagles were randomized to receive an infusion of saline or N-monomethyl-L-arginine (L-NMMA), a nonselective NO synthase (NOS) inhibitor, as a 40 mg kg bolus followed by a 40 mg kg(-1) h(-1) infusion for 3 to 6 h 3 h before (prophylactic) or 3 h after (therapeutic) challenge with TNF-alpha (60 microg kg(-1)) or vehicle. Serial radionuclide-heart scans and thermodilution pulmonary artery catheter hemodynamic measurements were performed. The effects of prophylactic L-NMMA on TNF-alpha-induced cardiac dysfunction as measured by decreases in mean left ventricular (LV) ejection fraction and downward and rightward shifts of LV function plots (peak systolic pressure versus end systolic volume index and LV stroke work index versus end diastolic volume index) were significantly different comparing early (3-6 h) and delayed (24 h) time points (P = 0.02). Prophylactic L-NMMA therapy did not appear to fully prevent early (3-6 h) TNF-alpha-induced cardiac dysfunction, but at 24 h, complete protection was seen. Therapeutic L-NMMA did not appear to fully protect the heart from TNF-alpha-induced early or delayed cardiac dysfunction (P = NS). Similarly, L-NMMA given prophylactically, but not therapeutically, blocked TNF-alpha-induced increases in exhaled NO flow rates and plasma nitrite and nitrate concentrations (both P = 0.02). These data suggest that TNF-alpha initiates two phases of cardiac injury: an early (3-6 h) phase that may be partially NO independent and a delayed (24 h) phase that is NO dependent. The delayed, more persistent dysfunction can be completely blocked by high doses of a nonselective NOS inhibitor administered before TNF-alpha.

Background: Previously, neutrophil stimulation with granulocyte colony-stimulating factor (G-CSF) pretreatment increased survival rates in canines challenged with intraperitoneal or intrabronchial Escherichia coli and in rats challenged with intrabronchial Staphylococcus aureus. We investigated whether G-CSF pretreatment would be beneficial with intravascular challenge in these models., Methods: Animals were randomized to G-CSF or placebo pretreatment followed by intravenous E. coli challenge in canines (n = 24) or intravenous or intrabronchial S. aureus challenge in rats (n = 273). All animals were treated with antibiotics., Results: In canines, G-CSF before intravenous E. coli did not decrease mortality rates (7 of 12 [58%] G-CSF vs. 5 of 12 [42%] controls), which contrasted with prior reductions during extravascular infection (10 of 35 [29%] G-CSF vs. 37 of 65 [57%] controls). Consistent with the present and previously published studies in canines, in rats, G-CSF decreased mortality rates with intrabronchial S. aureus (22 of 90 [24%] G-CSF vs. 26 of 51 [51%] controls, p = 0.009) but did not decrease them with intravenous infection (34 of 67 [50%] G-CSF vs. 27 of 65 [42%] controls, p = 0.2) in patterns that were very different (p = 0.005 for the effects of G-CSF with intravascular vs. intrabronchial S. aureus)., Conclusion: In contrast to extravascular infection, sepsis with intravascular E. coli in canines and S. aureus in rats may not provide a compartmentalized nidus of bacteria on which G-CSF-stimulated neutrophils can exert a beneficial antimicrobial effect. Extrapolated clinically, a proinflammatory agent like G-CSF may be most beneficial with sepsis related primarily to a compartmentalized extravascular site of infection.