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

AbstractOBJECTIVE:
To investigate the effect of blocking nitric oxide production on cardiovascular function and survival in canine septic 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 coli were surgically placed into the peritoneal cavity. N(omega)-monomethyl-L-arginine (L-NMMA) 10 mg/kg followed by 0.5, 1.0, or 4.0 mg/kg/hr), epinephrine (1 microg/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 increases in systemic vascular resistance index and mean arterial pressure 9 and 24 hrs after the onset of infection (p < or = .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 > or = .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.
AuthorsB D Freeman, F Zeni, S M Banks, P Q Eichacker, J D Bacher, E P Garvey, J V Tuttle, C H Jurgensen, C Natanson, R L Danner
JournalCritical care medicine (Crit Care Med) Vol. 26 Issue 5 Pg. 877-86 (May 1998) ISSN: 0090-3493 [Print] UNITED STATES
PMID9590318 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Drug Combinations
  • Enzyme Inhibitors
  • Vasoconstrictor Agents
  • omega-N-Methylarginine
  • Nitric Oxide
  • Nitric Oxide Synthase
  • Epinephrine
Topics
  • Animals
  • Dogs
  • Drug Combinations
  • Enzyme Inhibitors (therapeutic use)
  • Epinephrine (therapeutic use)
  • Escherichia coli Infections (drug therapy)
  • Hemodynamics (drug effects)
  • Nitric Oxide (biosynthesis, blood, metabolism)
  • Nitric Oxide Synthase (antagonists & inhibitors, metabolism)
  • Sepsis (drug therapy)
  • Vasoconstrictor Agents (therapeutic use)
  • omega-N-Methylarginine (therapeutic use)

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