Effects of TNF-alpha on hemodynamic changes and circulating endothelium-derived vasoactive factors in dogs.
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.
Mitaka
C
C
Department of Intensive Care, Tokyo Medical and Dental University, Japan.
Hirata
Y
Y
Ichikawa
K
K
Yokoyama
K
K
Emori
T
T
Kanno
K
K
Amaha
K
K
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D004285:Dogs; D016232:Endothelins / Q000097:blood*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009566:Nitrates / Q000097:blood*; D009573:Nitrites / Q000097:blood*; D019335:Nitroarginine; D011652:Pulmonary Circulation / Q000187:drug effects; D012016:Reference Values; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000493:pharmacokinetics / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects
D016232:Endothelins; D009566:Nitrates; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D019335:Nitroarginine; D015121:6-Ketoprostaglandin F1 alpha; D001120:Arginine; D007213:Indomethacin