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 ox ide synthase (iNOS) in the vascular wall accounts, at least in part, f or the severe hypotension in endotoxemia. The present study investigat ed whether 2-(allylthio)pyrazine (2-AP), an antioxidant, affects the L PS-induced expression of iNOS in rat aortic rings and the LPS-induced mortality in mice, 2-AP prevented the LPS-induced attenuation of contr actions to phenylephrine, formation of cyclic GMP, and expression of i NOS in aortic rings without endothelium and caused endothelium-depende nt nitric oxide-mediated relaxations. The mortality of mice receiving a lethal bolus of LPS was decreased by 2-AP, and this effect was assoc iated with a reduced serum nitrite and nitrate level, These findings s uggest that agents which inhibit the expression of iNOS but stimulate the formation of endothelium-derived nitric oxide may be of therapeuti cal value for the treatment of endotoxemia. (C) 1997 Academic Press.