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A. C. Burton Vascular Biology Laboratory, Departments of Respiratory Medicine, Pharmacology, and Toxicology, London Health Sciences Centre, University of Western Ontario, London, Ontario, Canada N6A 4G5
Elevated production of nitric oxide (NO) by the
inducible NO synthase (type II, iNOS) may contribute to the vascular
hyporesponsiveness and hemodynamic alterations associated with sepsis.
Selective inhibition of this isoenzyme is a possible therapeutic
intervention to correct these pathophysiological alterations.
Aminoguanidine has been shown to be a selective iNOS inhibitor and to
correct the endotoxin-mediated vascular hypocontractility in vitro.
However, to date aminoguanidine has not been shown to selectively block iNOS activity in vivo. The in vivo effects of aminoguanidine were assessed in the cecal ligation and perforation model of sepsis in rats.
Aminoguanidine (1.75-175 mg/kg) was administered to septic and
sham-operated rats for 3 h before euthanasia and harvest of tissues.
NOS activities were determined in the thoracic aorta and lung from
these animals. Aminoguanidine (17.5 mg/kg) did not alter the mean
arterial pressure; however, it did inhibit induced iNOS (but not
constitutive NOS) activity in the lung and thoracic aorta from septic
animals. Only the higher dose of aminoguanidine (175 mg/kg) was able to
increase the mean arterial pressure in septic and sham-operated
animals. Thus selective inhibition of iNOS in vivo with aminoguanidine
is possible, but our data suggest that other mechanisms, in addition to
iNOS induction, are responsible for the loss of vascular tone
characteristic of sepsis.
aminoguanidine; selective; enzyme inhibition
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