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


METHODS
Randomized, controlled trial.


METHODS
An animal research laboratory at the National Institutes of Health.


METHODS
Sixty purpose-bred beagles.


METHODS
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.


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.
Freeman
B D
BD
Critical Care Medicine Department, Warren G. Magnuson Clinical Center, Veterinary Resource Program, National Institutes of Health, Bethesda, MD 20892, USA.
Zeni
F
F
Banks
S M
SM
Eichacker
P Q
PQ
Bacher
J D
JD
Garvey
E P
EP
Tuttle
J V
JV
Jurgensen
C H
CH
Natanson
C
C
Danner
R L
RL
D000818:Animals; D004285:Dogs; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004837:Epinephrine / Q000627:therapeutic use*; D004927:Escherichia coli Infections / Q000188:drug therapy*; D006439:Hemodynamics / Q000187:drug effects; D009569:Nitric Oxide / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy*; D014662:Vasoconstrictor Agents / Q000627:therapeutic use*; D019323:omega-N-Methylarginine / Q000627:therapeutic use*
D004338:Drug Combinations; D004791:Enzyme Inhibitors; D014662:Vasoconstrictor Agents; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D004837:Epinephrine