Inhibitors of nitric oxide synthase (NOS) have been reported to increase mean arterial pressure in animal models of sepsis and recently have been given to patients in septic shock. However, controlled studies to determine the effects of these agents on cardiovascular function and survival in awake animal models of sepsis have not been reported. To examine the therapeutic potential of NOS inhibition in septic shock, we challenged canines with endotoxin (2 or 4 mg/kg i.v.) and treated them with either normal saline or N omega-amino-L-arginine (10 or 1 mg/kg/h), the most specific inhibitor available for the isoform of NOS implicated in septic shock. Endotoxemic animals treated with N omega-amino-L-arginine (n = 11) had higher systemic and pulmonary vascular resistance indices (SVRI and PVRI, p less than or equal to 0.033) and decreased heart rates (p = 0.009), cardiac indices (CI, p = 0.01), oxygen delivery indices (p = 0.027), and oxygen consumption indices (p = 0.046) compared with controls (n = 6). Moreover, N omega-amino-L-arginine increased mortality rates after endotoxin challenge (10 of 11 vs. 1 of 6 controls, p = 0.005). Administration of L-arginine did not improve survival or alter the cardiopulmonary effects of N omega-amino-L-arginine, which suggests that inhibition of NOS may not have been competitive. In normal animals, N omega-amino-L-arginine alone (n = 3) increased SVRI (p = 0.0008) and mean arterial pressure (p = 0.016), and decreased CI (p = 0.01) compared with saline-treated controls (n = 3), but, at the high dose, also produced neuromuscular rigidity and seizure-like activity that was not apparent in the endotoxemic model. Thus, the mortality rate from endotoxemia increased either because of NOS inhibition per se or because of properties unique to N omega-amino-L-arginine, or both.
Article|
October 01 1992
N omega-amino-L-arginine, an inhibitor of nitric oxide synthase, raises vascular resistance but increases mortality rates in awake canines challenged with endotoxin.
J P Cobb,
J P Cobb
Department of Critical Care Medicine, Warren G. Magnusen Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
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C Natanson,
C Natanson
Department of Critical Care Medicine, Warren G. Magnusen Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
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W D Hoffman,
W D Hoffman
Department of Critical Care Medicine, Warren G. Magnusen Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
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R F Lodato,
R F Lodato
Department of Critical Care Medicine, Warren G. Magnusen Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
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S Banks,
S Banks
Department of Critical Care Medicine, Warren G. Magnusen Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
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C A Koev,
C A Koev
Department of Critical Care Medicine, Warren G. Magnusen Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
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M A Solomon,
M A Solomon
Department of Critical Care Medicine, Warren G. Magnusen Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
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R J Elin,
R J Elin
Department of Critical Care Medicine, Warren G. Magnusen Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
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J M Hosseini,
J M Hosseini
Department of Critical Care Medicine, Warren G. Magnusen Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
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R L Danner
R L Danner
Department of Critical Care Medicine, Warren G. Magnusen Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
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J P Cobb
Department of Critical Care Medicine, Warren G. Magnusen Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
C Natanson
Department of Critical Care Medicine, Warren G. Magnusen Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
W D Hoffman
Department of Critical Care Medicine, Warren G. Magnusen Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
R F Lodato
Department of Critical Care Medicine, Warren G. Magnusen Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
S Banks
Department of Critical Care Medicine, Warren G. Magnusen Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
C A Koev
Department of Critical Care Medicine, Warren G. Magnusen Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
M A Solomon
Department of Critical Care Medicine, Warren G. Magnusen Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
R J Elin
Department of Critical Care Medicine, Warren G. Magnusen Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
J M Hosseini
Department of Critical Care Medicine, Warren G. Magnusen Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
R L Danner
Department of Critical Care Medicine, Warren G. Magnusen Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
Online ISSN: 1540-9538
Print ISSN: 0022-1007
J Exp Med (1992) 176 (4): 1175–1182.
Citation
J P Cobb, C Natanson, W D Hoffman, R F Lodato, S Banks, C A Koev, M A Solomon, R J Elin, J M Hosseini, R L Danner; N omega-amino-L-arginine, an inhibitor of nitric oxide synthase, raises vascular resistance but increases mortality rates in awake canines challenged with endotoxin.. J Exp Med 1 October 1992; 176 (4): 1175–1182. doi: https://doi.org/10.1084/jem.176.4.1175
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