Prophylactic high-dose N(omega)-monomethyl-L-arginine prevents the late cardiac dysfunction associated with lethal tumor necrosis factor-alpha challenge in dogs.
We investigated nitric oxide (NO) as a possible cause of the cardiac dysfunction associated with high, lethal doses of tumor necrosis factor-alpha (TNF-alpha) in dogs. Eighty-seven awake, 2-year-old (10-12 kg), purpose-bred beagles were randomized to receive an infusion of saline or N-monomethyl-L-arginine (L-NMMA), a nonselective NO synthase (NOS) inhibitor, as a 40 mg kg bolus followed by a 40 mg kg(-1) h(-1) infusion for 3 to 6 h 3 h before (prophylactic) or 3 h after (therapeutic) challenge with TNF-alpha (60 microg kg(-1)) or vehicle. Serial radionuclide-heart scans and thermodilution pulmonary artery catheter hemodynamic measurements were performed. The effects of prophylactic L-NMMA on TNF-alpha-induced cardiac dysfunction as measured by decreases in mean left ventricular (LV) ejection fraction and downward and rightward shifts of LV function plots (peak systolic pressure versus end systolic volume index and LV stroke work index versus end diastolic volume index) were significantly different comparing early (3-6 h) and delayed (24 h) time points (P = 0.02). Prophylactic L-NMMA therapy did not appear to fully prevent early (3-6 h) TNF-alpha-induced cardiac dysfunction, but at 24 h, complete protection was seen. Therapeutic L-NMMA did not appear to fully protect the heart from TNF-alpha-induced early or delayed cardiac dysfunction (P = NS). Similarly, L-NMMA given prophylactically, but not therapeutically, blocked TNF-alpha-induced increases in exhaled NO flow rates and plasma nitrite and nitrate concentrations (both P = 0.02). These data suggest that TNF-alpha initiates two phases of cardiac injury: an early (3-6 h) phase that may be partially NO independent and a delayed (24 h) phase that is NO dependent. The delayed, more persistent dysfunction can be completely blocked by high doses of a nonselective NOS inhibitor administered before TNF-alpha.
Sevransky
Jonathan
J
Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland, USA. sevransj@jhmi.edu
Vandivier
R William
RW
Gerstenberger
Eric
E
Correa
Rosalee
R
Ferantz
Victor
V
Banks
Steven M
SM
Danner
Robert L
RL
Eichacker
Peter Q
PQ
Natanson
Charles
C
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006331:Heart Diseases / Q000139:chemically induced* / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control*; D006339:Heart Rate / Q000187:drug effects; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009573:Nitrites / Q000097:blood; D013318:Stroke Volume / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*; D014655:Vascular Resistance / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects; D019323:omega-N-Methylarginine / Q000008:administration & dosage* / Q000627:therapeutic use
D004791:Enzyme Inhibitors; D009566:Nitrates; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase