Effects of L-NMMA and fluid loading on TNF-induced cardiovascular dysfunction in dogs

Zenaide M.N. Quezado, Waheedullah Karzai, Robert L. Danner, Bradley D. Freeman, Liang Yan, Peter Q. Eichacker, Steven M. Banks, J. Perren Cobb, Robert E. Cunnion, Marcelo J.N. Quezado, Jonathan E. Sevransky, Charles Natanson

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Abstract

We investigated the effects of Nω-monomethyl-L-arginine (L-NMMA) and fluid loading on tumor necrosis factor (TNF)-induced cardiovascular dysfunction in awake dogs. L-NMMA (40 mg · kg-1 given intravenously over a period of 10 min, and followed by dosing at 40 mg · kg-1 · h-1 for 6 h) and TNF (20 or 45 μg · 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 · 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.

Original languageEnglish
Pages (from-to)1397-1405
Number of pages9
JournalAmerican journal of respiratory and critical care medicine
Volume157
Issue number5 PART I
StatePublished - Dec 1 1998
Externally publishedYes

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    Quezado, Z. M. N., Karzai, W., Danner, R. L., Freeman, B. D., Yan, L., Eichacker, P. Q., Banks, S. M., Cobb, J. P., Cunnion, R. E., Quezado, M. J. N., Sevransky, J. E., & Natanson, C. (1998). Effects of L-NMMA and fluid loading on TNF-induced cardiovascular dysfunction in dogs. American journal of respiratory and critical care medicine, 157(5 PART I), 1397-1405.