Journal of Antimicrobial Chemotherapy, Vol 41, 31-39, Copyright © 1998 by The British Society for Antimicrobial Chemotherapy
JR Parratt
Nitric oxide (NO) is one of many vasoactive substances released, from a
variety of cells, under conditions of endotoxaemia and sepsis. Under
physiological conditions it is produced by two constitutive calcium-
dependent enzymes (nitric oxide synthase; NOS) in neurones (nNOS) and
endothelial cells (eNOS) and has functions ranging from neurotransmission
and vasodilatation to inhibition of platelet adhesion and aggregation.
Following bacterial infection, especially with Gram- negative organisms,
its formation from L-arginine is enhanced due to the cytokine-mediated
induction of a NOS enzyme (iNOS) in cells (e.g. cardiac myocytes, vascular
smooth muscle) that do not normally have the ability to synthesize NO. The
result of this excessive NO production is enhanced bacterial lysis by
activated macrophages, vasoplegia and myocardial depression. These
cardiovascular effects can be alleviated by inhibitors of the L-arginine NO
pathway, which results in elevated perfusion pressure, restored
responsiveness to sympathetic nerve stimulation and to exogenous
catecholamines, and to enhanced (endothelin-dependent) myocardial
contractility. In patients in shock this approach also leads to detrimental
effects (increased systemic vascular resistance, elevated pulmonary artery
pressure, reduced cardiac output and oxygen delivery, increased platelet
accumulation) and survival is not improved. Because some of these
detrimental effects are due to inhibition of eNOS, attempts have been made
to examine the effects of substances with a higher selectivity for the
induced form of the enzyme. In experimental animals, one of these
(L-canavanine) protects endothelial cells from damage, increases survival
time and restores vascular responsiveness without increasing blood pressure
or peripheral vascular resistance. However, whether even this approach will
be of benefit to patients with sepsis remains in doubt since studies in
iNOS knock-out mice do not support the concept that eliminating this
particular source of NO improves ultimate survival.
ORIGINAL ARTICLES
Nitric oxide in sepsis and endotoxaemia
Department of Physiology and Pharmacology, University of Strathclyde, Royal College, Glasgow, UK.
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