Inducible nitric oxide synthase and vascular reactivity in rat thoracic aorta: effect of aminoguanidine.
We tested the hypothesis that selective inhibition of the inducible form of nitric oxide (NO) synthase with aminoguanidine would prevent the loss of vascular contractility after exposure to endotoxin [lipopolysaccharide (LPS)]. Aortic rings were dissected from Sprague-Dawley rats, suspended in organ baths containing Krebs solution, and tested for vascular reactivity. Vessels incubated with LPS (1 microgram/ml) for 5 h exhibited a significant decrease in the maximal contractile response to phenylephrine. Aminoguanidine (100 microM) restored the maximal contractile response of LPS-treated vessels to the level of the control vessels. Aminoguanidine was approximately 250-fold less potent than NG-nitro-L-arginine methyl ester in inhibiting the constitutive NO synthase in vascular tissue as determined by its ability to further increase tone of submaximally contracted aortic rings. NO synthase activity was determined in vascular tissue incubated with and without LPS. Vessels incubated with LPS exhibited a marked increase in the levels of inducible NO synthase activity compared with control vessels. This increase was restored to control levels when tissue homogenates were incubated with aminoguanidine. We conclude that aminoguanidine is a selective concentration-dependent inhibitor of the inducible form of NO synthase and may be a useful probe to evaluate the role of inducible NO synthase in the abnormal vascular contractility characteristic of endotoxemia and sepsis.
Scott
J A
JA
Department of Medicine, University of Western Ontario, London, Canada.
Machoun
M
M
McCormack
D G
DG
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000201:enzymology; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology*; D019331:NG-Nitroarginine Methyl Ester; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D010656:Phenylephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D004791:Enzyme Inhibitors; D006146:Guanidines; D008070:Lipopolysaccharides; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D011189:Potassium Chloride; D001120:Arginine; D019001:Nitric Oxide Synthase; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester