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.