Effects of TNF-alpha on hemodynamic changes and circulating endothelium-derived vasoactive factors in dogs

Am J Physiol. 1994 Oct;267(4 Pt 2):H1530-6. doi: 10.1152/ajpheart.1994.267.4.H1530.


To elucidate the relation of tumor necrosis factor-alpha (TNF-alpha)-induced hemodynamic change to endothelium-derived vasoactive factors, we simultaneously measured hemodynamic parameters and circulating endothelin (ET)-1, ET-3, nitrite/nitrate (NOx), and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) in anesthetized dogs following administration of TNF-alpha with or without NG-nitro-L-arginine (L-NNA), a nitric oxide (NO) synthase inhibitor, and indomethacin, a cyclooxygenase inhibitor. Natural human TNF-alpha (10 micrograms/kg, n = 5) with or without L-NNA (1 mg/kg, n = 5) or indomethacin (2 mg/kg, n = 5) was administered intravenously as a bolus, while administration of vehicle served as control (n = 5). After administration of TNF-alpha, mean arterial pressure and cardiac index significantly decreased, whereas systemic (SVRI) and pulmonary (PVRI) vascular resistance index increased. Plasma levels of ET-1, ET-3, NOx, and 6-keto-PGF1 alpha significantly (P < 0.01) increased at 1 h. L-NNA or indomethacin blocked TNF-alpha-induced hypotension and remarkably increased SVRI but did not affect decreased cardiac index. Our data suggest that endogenous ET-1 may partly contribute to TNF-alpha-induced increases in SVRI and PVRI, against which ET-3, NO, and prostacyclin may function as compensatory vasodilators.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 6-Ketoprostaglandin F1 alpha / blood
  • Animals
  • Arginine / analogs & derivatives
  • Arginine / pharmacology
  • Blood Pressure / drug effects
  • Cardiac Output / drug effects
  • Dogs
  • Endothelins / blood*
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / physiology*
  • Female
  • Hemodynamics / drug effects*
  • Humans
  • Indomethacin / pharmacology
  • Male
  • Nitrates / blood*
  • Nitrites / blood*
  • Nitroarginine
  • Pulmonary Circulation / drug effects
  • Reference Values
  • Time Factors
  • Tumor Necrosis Factor-alpha / pharmacokinetics
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Vascular Resistance / drug effects


  • Endothelins
  • Nitrates
  • Nitrites
  • Tumor Necrosis Factor-alpha
  • Nitroarginine
  • 6-Ketoprostaglandin F1 alpha
  • Arginine
  • Indomethacin