Sepsis nitric-oxide synthase

B42. Booke, M., Hinder, F., McGuire, R., Traber, L. D., and Traber, D. L Nitric oxide synthase inhibition versus norepinephrine for the treatment of hyperdynamic sepsis in sheep. Crit. Care Med. 24, 835-844 (1996). 

To set up and validate the in vitro systems we initiated a study with rat Uver slices. Stimulation by Upopolysaccharide (LPS) in liver slices was used to evoke a pro-inflammatory response in the Uver. Lipopolysaccharide (LPS), a component of Gram-negative bacterial ceU walls (also called endotoxin), has been associated with tissue injury and sepsis. In the Uver LPS activates the resident macrophages, the Kupffer ceUs, which results in cytokine release [96]. Furthermore, LPS is cleared by the Uver, mainly by Kupffer ceUs [97]. One of the major features of endotoxic shock is the induction of nitric oxide S5mthase in the Uver [98]. Inducible nitric oxide synthase (iNOS), the expression of which is induced by LPS and cytokines, produces nitric oxide (NO) in large quantities [99]. 

Many pathological conditions, including ischemia/reperfusion, inflammation, and sepsis may induce tissues to simultaneously produce both superoxide and nitric oxide. For example, ischemia allows intracellular calcium to accumulate in endothelium (Fig. 20). If the tissue is reperfused, the readmission of oxygen will allow nitric oxide as well as superoxide to be produced (Beckman, 1990). For each 10-fold increase in the concentration of nitric oxide and superoxide, the rate of peroxynitrite formation will increase by 100-fold. Sepsis causes the induction of a second nitric oxide synthase in many tissues, which can produce a thousand times more nitric oxide than the normal levels of the constitutive enzyme (Moncada et al., 1991). Nitric oxide and indirectly peroxynitrite have been implicated in several important disease states. Blockade of nitric oxide synthesis with N-methyl or N-nitroarginine reduces glutamate-induced neuronal degeneration in primary cortical cultures (Dawson et al., 1991). Nitroarginine also decreases cortical infarct volume by 70% in mice subjected to middle cerebral artery occlusion (Nowicki et al., 1991). Myocardial injury from a combined hy-... 

Spain DA, Wilson MA, Garrison RN (1994) Nitric oxide synthase inhibition exacerbates sepsis-induced renal hypoperfusion. Surgery 116 322-331. 

J.M. Wong, T.R. Billiar, Regulation andfunction of inducible nitric oxide synthase during sepsis and acute inflammation, L. Ignarro and F. Murad Eds, 155-170, Academic press, San Diego 1995. 

Evans, T., Carpenter, A., Silva, A., and Cohen, J. (1992). Differential effects of monoclonal antibodies to tumor necrosis factor alpha and gamma interferon on induction of hepatic nitric oxide synthase in experimental gram-negative sepsis./n/ect. Immun. 60,4133-4139. 

Regulation and Function of Inducible Nitric Oxide Synthase during Sepsis and Acute Inflammation... 

Bakker, J., Grover, R., McLuckie, A., Holzapfel, L., Andersson, J., Lodato, R., Watson, D., Grossman, S., Donaldson, J., and Takala, J. (2004). Administration of the nitric oxide synthase inhibitor NG-methyl-L-aiginine hydrochloride (546C88) by intravenous infusion for up to 72 hours can promote the resolution of shock in patients with severe sepsis results of a randomized, double-blind, placebo-controlled multicenler study (study no. 144-002). Crit. Care Med. 32,1-12. 

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