Inhibition of inducible nitric oxide synthase expression and stimulation of the endothelial formation of nitric oxide most likely accounts for the protective effect of 2-(allylthio)pyrazine in a murine model of endotoxemia.
The lipopolysaccharide (LPS)-induced expression of inducible nitric oxide synthase (iNOS) in the vascular wall accounts, at least in part, for the severe hypotension in endotoxemia. The present study investigated whether 2-(allylthio)pyrazine (2-AP), an antioxidant, affects the LPS-induced expression of iNOS in rat aortic rings and the LPS-induced mortality in mice. 2-AP prevented the LPS-induced attenuation of contractions to phenylephrine, formation of cyclic GMP, and expression of iNOS in aortic rings without endothelium and caused endothelium-dependent nitric oxide-mediated relaxations. The mortality of mice receiving a lethal bolus of LPS was decreased by 2-AP, and this effect was associated with a reduced serum nitrite and nitrate level. These findings suggest that agents which inhibit the expression of iNOS but stimulate the formation of endothelium-derived nitric oxide may be of therapeutical value for the treatment of endotoxemia.
Kim
N D
ND
College of Pharmacy, Seoul National University, Korea.
Kang
K W
KW
Kim
S G
SG
Schini-Kerth
V B
VB
D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D019446:Endotoxemia / Q000201:enzymology* / Q000401:mortality; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D009573:Nitrites / Q000097:blood; D009924:Organ Culture Techniques; D010656:Phenylephrine / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
C104935:2-(allylthio)pyrazine; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D009566:Nitrates; D009573:Nitrites; D011719:Pyrazines; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP