Response of the septic vasculature to prolonged vasopressor therapy with N(ω)-monomethyl-l-arginine and epinephrine in canines

Bradley D. Freeman, Fabrice Zeni, Steven M. Banks, Peter Q. Eichacker, John D. Bacher, Edward P. Garvey, Joel V. Tuttle, Cynthia H. Jurgensen, Charles Natanson, Robert L. Danner

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


Objective: To investigate the effect of blocking nitric oxide production on cardiovascular function and survival in canine sep- tic shock treated with or without a conventional vasopressor. Design: Randomized, controlled trial. Setting: An animal research laboratory at the National Institutes of Health. Subjects: Sixty purpose-bred beagles. Interventions: Fibrin clots containing Escherichia coil were surgically placed into the peritoneal cavity. N(ω)- monomethyI-L-arginine (L-NMMA) 10 mg/kg followed by 0.5, 1.0, or 4.0 mg/kg/hr), epinephrine (1 μg/kg/min), both, or neither were infused for 24 hrs beginning 6 hrs after the onset of infection. All animals received fluid and antibiotic therapy. Measurements and Main Results: Serum nitric oxide metabolites, nitrite and nitrate, increased with infection (p = .024) and decreased with L-NMMA (p = .004, all doses combined). Myocardial nitric oxide synthase activity was ranked as follows: nonsurvivors > survivors > noninfected controls (p < .01). Other tissues examIned showed the same pattern. L-NMMA produced sustained in creases in systemic vascular resistance index and mean arterial pressure 9 and 24 hrs after the onset of infection (p < .04). Left ventricular ejection fraction was depressed by septic shock (p = .01) and further decreased by L-NMMA (p = .02). However, control and L-NMMA cardiac index values were similar (p > .4), perhaps because L-NMMA increased pulmonary artery occlusion pressure (p = .02). From 9 to 24 hrs, epinephrine, in the absence or presence of L-NMMA, blunted recovery of cardiac index (p < .02) and had a diminishing vasopressor effect (p = .05). Neither L-NMMA nor epinephrine, individually or combined, significantly altered survival rates at the doses investigated (p ≤ .69). Conclusions: The tested doses showed that nitric oxide production was inhibited by L-NMMA in canine septic shock, but mortality and myocardial depression were unaffected. These results suggest that if L-NMMA has a beneficial effect on survival rates in septic shock, it is small.

Original languageEnglish
Pages (from-to)877-886
Number of pages10
JournalCritical care medicine
Issue number5
StatePublished - May 19 1998


  • Endotoxin
  • Epinephrine
  • Hemodynamics
  • Nitric oxide
  • Sepsis
  • Septic shock
  • Survival
  • Tumor necrosis factor


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