The role of tumor necrosis factor and nitric oxide in the acute cardiovascular response to endotoxin.
OBJECTIVE
This study was designed to examine the differential effects of tumor necrosis factor (TNF) and nitric oxide on the acute cardiovascular changes that occur in response to endotoxemia.


BACKGROUND
Recent studies have suggested that some, if not all, of the cardiovascular effects of TNF are mediated through release of nitric oxide. However, the mechanisms through which TNF and nitric oxide induce hypotension and shock in vivo in response to systemic endotoxemia remain poorly characterized, despite current interest in the use of nitric oxide antagonists to ameliorate septic shock.


METHODS
A reproducible model of endotoxemia was established in adult Sprague-Dawley rats. The acute cardiovascular changes that occur after bolus infusion of endotoxin was then determined in rats treated with either TNF antibody, N-methyl arginine, or both.


RESULTS
Inhibition of either TNF or nitric oxide restores mean arterial blood pressure to normal after endotoxemia (p < 0.05). However, nitric oxide exerts its effects principally on the peripheral vasculature, whereas TNF appears to act on the myocardium. A combination of TNF antiserum pretreatment and N-methyl arginine administration is necessary to return mean arterial blood pressure to normal 60 minutes after endotoxin infusion.


CONCLUSIONS
Tumor necrosis factor and nitric oxide mediate the acute cardiovascular effects of endotoxemia through distinct mechanisms. Nitric oxide is released as a result of both TNF-dependent and TNF-independent mechanisms, whereas the cardiovascular effects of TNF are only partially mediated through nitric oxide.
Fahey
T J
TJ
Department of Surgery, New York Hospital-Cornell Medical Center, New York, USA.
Yoshioka
T
T
Shires
G T
GT
Fantini
G A
GA
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002318:Cardiovascular Diseases / Q000503:physiopathology*; D004731:Endotoxins / Q000008:administration & dosage; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000494:pharmacology / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000503:physiopathology*; D014115:Toxemia / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*
D004731:Endotoxins; D004791:Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester