Selective inhibition of the inducible nitric oxide synthase by aminoguanidine.
Overproduction of the free radical nitric oxide (NO) has been implicated in the pathogenesis of a variety of inflammatory and immunologically mediated diseases as well as complications of diabetes. In the present study we have demonstrated that aminoguanidine selectively inhibits the cytokine-inducible isoform of NO synthase which appears to be responsible for the excess production of NO linked to these disease states. By using organ, cell, and enzyme-based measurements we have shown that aminoguanidine is equipotent to NG-monomethyl-L-arginine (L-NMA) as an inhibitor of the cytokine-induced isoform of NO synthase but is 10 to 100-fold less potent as an inhibitor of the constitutive isoform. Thus, aminoguanidine may be useful as a selective inhibitor of the inducible NO synthase in the treatment of disease states characterized by the pathological overproduction of NO.
Misko
T P
TP
Department of Molecular Pharmacology, Monsanto Corporate Research, St. Louis, MO 63167.
Moore
W M
WM
Kasten
T P
TP
Nickols
G A
GA
Corbett
J A
JA
Tilton
R G
RG
McDaniel
M L
ML
Williamson
J R
JR
Currie
M G
MG
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001120:Arginine / Q000378:metabolism; D002478:Cells, Cultured; D002956:Citrulline / Q000378:metabolism; D006152:Cyclic GMP / Q000096:biosynthesis; D006146:Guanidines / Q000494:pharmacology*; D008264:Macrophages / Q000201:enzymology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000201:enzymology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase; D009573:Nitrites / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013050:Spectrometry, Fluorescence
D006146:Guanidines; D009573:Nitrites; D002956:Citrulline; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D006152:Cyclic GMP; C004479:pimagedine