title: Effects of L-NMMA and fluid loading on TNF-induced cardiovascular dysfunction in dogs.
abstract: We investigated the effects of N(omega)-monomethyl-L-arginine (L-NMMA) and fluid loading on tumor necrosis factor (TNF)-induced cardiovascular dysfunction in awake dogs. L-NMMA (40 mg x kg(-1) given intravenously over a period of 10 min, and followed by dosing at 40 mg x kg(-1) x h(-1) for 6 h) and TNF (20 or 45 microg x kg(-1) given intravenously for 20 min), given alone or in combination, significantly decreased stroke volume, cardiac index, oxygen delivery, and left-ventricular (LV) function plots over a period of 6 h. Of note was that the cardiac-depressant effects of TNF and L-NMMA given together were significantly less than additive. Thus, the combination was beneficial (or significantly less harmful to cardiac performance than expected), possibly because L-NMMA augmented cardiac preload as shown by significant increases in both pulmonary capillary wedge pressure (PCWP) and central venous pressure (CVP). Fluid challenges at 6 h (Ringer's solution at 80 ml x kg(-1) given over a period of 30 min) also significantly increased PCWP and CVP, and abolished the beneficial preload effect of L-NMMA on cardiac performance. Thus, after fluid loading, the cardiac-depressant effects of TNF and L-NMMA given together became equal to the sum of those produced by TNF and L-NMMA given separately. Although L-NMMA significantly decreased serum nitrite/nitrate levels, TNF did not increase these end products of nitric oxide (NO) production relative to controls. Therefore, after preload abnormalities were eliminated with fluid loading, L-NMMA had no beneficial effect on TNF-induced cardiac depression, and TNF did not increase end products of NO production. These findings are not consistent with NO being the mechanism of TNF-induced acute cardiac depression.
authors.affiliation: Critical Care Medicine Department, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Z M
authors.initials: ZM
authors.lastname: Quezado
authors.forename: W
authors.initials: W
authors.lastname: Karzai
authors.forename: R L
authors.initials: RL
authors.lastname: Danner
authors.forename: B D
authors.initials: BD
authors.lastname: Freeman
authors.forename: L
authors.initials: L
authors.lastname: Yan
authors.forename: P Q
authors.initials: PQ
authors.lastname: Eichacker
authors.forename: S M
authors.initials: SM
authors.lastname: Banks
authors.forename: J P
authors.initials: JP
authors.lastname: Cobb
authors.forename: R E
authors.initials: RE
authors.lastname: Cunnion
authors.forename: M J
authors.initials: MJ
authors.lastname: Quezado
authors.forename: J E
authors.initials: JE
authors.lastname: Sevransky
authors.forename: C
authors.initials: C
authors.lastname: Natanson
mesh_terms: D000818:Animals; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D007022:Hypotension / Q000139:chemically induced / Q000503:physiopathology*; D007262:Infusions, Intravenous; D007552:Isotonic Solutions / Q000008:administration & dosage; D011669:Pulmonary Wedge Pressure / Q000187:drug effects; D000077331:Ringer's Solution; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*; D014690:Venous Pressure / Q000187:drug effects; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000503:physiopathology*; D014882:Water-Electrolyte Balance; D019323:omega-N-Methylarginine / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D007552:Isotonic Solutions; D014409:Tumor Necrosis Factor-alpha; D019323:omega-N-Methylarginine; D000077331:Ringer's Solution