Dissociation of TNF-alpha from endotoxin-induced nitric oxide and acute-phase hypotension

Am J Physiol. 1997 Jul;273(1 Pt 2):H164-74. doi: 10.1152/ajpheart.1997.273.1.H164.


We tested the concept that tumor necrosis factor-alpha (TNF-alpha) or platelet-activating factor (PAF) mediated Escherichia coli endotoxin lipopolysaccharide (LPS)-induced upregulation of nitric oxide (NO) and acute-phase hypotension (APH) in the rat. LPS (0.5 mg/kg i.v.) given to rats treated with saline or nonimmune goat-derived gamma-globulin (immunoglobulin G, 22 mg/kg i.m.) produced APH and increased plasma concentrations of TNF-alpha and nitrate and nitrite anions (reactive nitrogen intermediates; RNI) and NO in ex vivo incubates of polymorphonuclear neutrophils (PMN) and inducible NO synthase (iNOS) mRNA in PMN. Pretreatment of rats with a polyclonal TNF-alpha antibody (TNF-Ab, 22 mg/kg i.m.) abolished LPS-mediated increases in plasma TNF-alpha but failed to inhibit APH or the NO system. TNF-alpha (8.2 micrograms/kg i.v.) produced transient hypertension and sustained tachycardia and increased plasma TNF-alpha and PMN iNOS mRNA but not RNI. LPS and TNF-alpha decreased spontaneous and calcimycin (Ca2+ ionophore, 1 microM)- and PAF (1 microM)-mediated increases in head-space NO production by rings of mesenteric artery incubated ex vivo. TNF-Ab abolished all effects of TNF-alpha. PAF (25, 50, and 100 ng/kg) produced APH without increasing plasma TNF-alpha, RNI, or PMN iNOS mRNA. The PAF receptor antagonist BN-50730 (80 micrograms/kg i.v.) abolished PAF-induced APH and attenuated LPS-induced increases in RNI. We conclude that 1) LPS produces parallel but unrelated changes in TNF-alpha and RNI in plasma and PMN during the APH of endotoxemia; and 2) endogenous TNF-alpha is not required for LPS-mediated induction of iNOS mRNA, and PAF mediates LPS-induced APH.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Azepines / pharmacology
  • Blood Pressure / drug effects
  • Endotoxins / toxicity*
  • Enzyme Induction
  • Escherichia coli
  • Heart Rate / drug effects
  • Hypotension / chemically induced
  • Hypotension / physiopathology*
  • Immunoglobulin G / pharmacology
  • Lipopolysaccharides / toxicity*
  • Male
  • Mesenteric Arteries / drug effects
  • Mesenteric Arteries / physiology
  • Mesenteric Arteries / physiopathology*
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / physiology
  • Muscle, Smooth, Vascular / physiopathology*
  • Neutrophils / drug effects
  • Neutrophils / physiology*
  • Nitric Oxide / biosynthesis
  • Nitric Oxide Synthase / biosynthesis*
  • Platelet Activating Factor / pharmacology
  • Platelet Aggregation Inhibitors / pharmacology
  • RNA, Messenger / biosynthesis
  • Rats
  • Rats, Sprague-Dawley
  • Thienopyridines
  • Time Factors
  • Transcription, Genetic / drug effects
  • Triazoles / pharmacology
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / physiology*


  • Azepines
  • Endotoxins
  • Immunoglobulin G
  • Lipopolysaccharides
  • Platelet Activating Factor
  • Platelet Aggregation Inhibitors
  • RNA, Messenger
  • Thienopyridines
  • Triazoles
  • Tumor Necrosis Factor-alpha
  • BN 50730
  • Nitric Oxide
  • Nitric Oxide Synthase