Effect of a nitric oxide synthase inhibitor, S-ethylisothiourea, on cultured cells and cardiovascular functions of normal and lipopolysaccharide-treated rabbits.
Nitric oxide (NO) is synthesized from L-arginine by three isoforms of NO synthase (NOS). It is essential to suppress the function of the inducible isoform (macNOS) for amelioration of some inflammatory diseases in which the cytotoxic effect of NO is involved. S-Ethylsiothiourea (S-EIU) was reported to be a potent and specific inhibitor of macNOS. We also confirmed that it rather specifically inhibited the activity of the purified macNOS and the formation of nitrite by RAW264.7 cells compared to NG-monomethyl-L-arginine (L-NMA) and NG-nitro-L-arginine (L-NNA), the other isoforms being less effective. S-EIU suppressed the release of nitrite and lactate dehydrogenase from rat vascular smooth muscle cells treated with interleukin-1 beta and forskolin more potently than L-NMA or L-NNA. S-EIU also slightly suppressed internucleosomal DNA cleavage in pancreatic beta-cells induced by NO produced by macNOS. Intravenous administration of either S-EIU at 0.1 mg/kg/min or L-NMA at 1 mg/kg/min increased the blood pressure but decreased the heart rate in normal rabbits, while aminoguanidine at 1 mg/kg/min affected neither cardiovascular function. These inhibitors at these doses caused recovery of the blood pressure in lipopolysaccharide-treated rabbits that exhibited lowered blood pressure similar to that in the case of septic shock. Although S-EIU seemed not to be an adequate inhibitor for therapeutic use in vivo due to its side effects on cardiovascular functions, it is one of the most potent inhibitors of macNOS among reported inhibitors in vitro.
Seo
H G
HG
Department of Biochemistry, Osaka University Medical School.
Fujiwara
N
N
Kaneto
H
H
Asahi
M
M
Fujii
J
J
Taniguchi
N
N
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D001921:Brain / Q000201:enzymology; D002478:Cells, Cultured; D002956:Citrulline / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects*; D007375:Interleukin-1 / Q000494:pharmacology; D007550:Isothiuronium / Q000031:analogs & derivatives* / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D009707:Nucleosomes / Q000235:genetics; D011817:Rabbits; D051381:Rats; D012772:Shock, Septic / Q000503:physiopathology
D004791:Enzyme Inhibitors; D007375:Interleukin-1; D008070:Lipopolysaccharides; D009573:Nitrites; D009707:Nucleosomes; D005576:Colforsin; D007550:Isothiuronium; C007687:etiron; D002956:Citrulline; D004247:DNA; D007770:L-Lactate Dehydrogenase; D019001:Nitric Oxide Synthase