Reversal of endotoxin-mediated shock by NG-methyl-L-arginine, an inhibitor of nitric oxide synthesis.
Septic shock is a life-threatening condition that results from exposure to bacterial endotoxin. It is manifested by cardiovascular collapse and mediated by the release of cytokines such as tumor necrosis factor. Some of these cytokines cause the release of vasoactive substances. In the present study, administration of 40 microgram/kg of bacterial endotoxin to dogs caused a 33% decrease in peripheral vascular resistance and a 54% fall in mean arterial blood pressure within 30 to 90 minutes. Vascular resistance and systemic arterial pressure returned to normal within 1.5 minutes after intravenous administration of NG-methyl-L-arginine (20 mg/kg), a potent and selective inhibitor of nitric oxide synthesis. L-Arginine reversed the effect of L-NMA and restored the endotoxin-induced hypotension. Although NG-methyl-L-arginine injection increased blood pressure in control dogs, the hypertensive effect was much greater in endotoxemic dogs (24.8 +/- 2.7 mmHg vs 47.8 +/- 6.8 mmHg, p = 0.01, n = 4). NG-Methyl-L-arginine caused only a modest increase in blood pressure in dogs made hypotensive by continuous intravenous infusion of nitroglycerin (17.1 +/- 5.0 mm Hg, n = 3). These findings suggest that nitric oxide overproduction is an important contributor to endotoxic shock. Moreover, our findings demonstrate for the first time, the utility of nitric oxide synthesis inhibitors in endotoxic shock and suggest that such inhibitors may be of therapeutic value in the treatment of septic shock.
Kilbourn
R G
RG
University of Texas M.D. Anderson Cancer Center, Department of Medical Oncology, Houston 77030.
Jubran
A
A
Gross
S S
SS
Griffith
O W
OW
Levi
R
R
Adams
J
J
Lodato
R F
RF
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001794:Blood Pressure; D016207:Cytokines / Q000494:pharmacology; D004285:Dogs; D004731:Endotoxins / Q000494:pharmacology*; D005260:Female; D006973:Hypertension / Q000139:chemically induced; D007700:Kinetics; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D012772:Shock, Septic / Q000139:chemically induced* / Q000188:drug therapy; D014655:Vascular Resistance / Q000187:drug effects; D019323:omega-N-Methylarginine
D016207:Cytokines; D004731:Endotoxins; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine