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Bahrami Soheyl; Fitzal, Florian; Peichl, Gerd; Gasser, Harald; Fuerst, Walter; Banerjee, Asmita; Strohmaier, Wolfgang; Redl, Heinz; Werner-Felmayer, Gabriela; Werner, Ernst R.
Shock: May 2000
Basic Science Investigations: PDF Only
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ABSTRACT

We studied the effects of a novel pterin antagonist of NO synthase, the 4-amino analogue of tetrahydrobiopterin (4-ABH4), in a rat model of endotoxic shock and compared its properties with those of NG-monomethyl L-arginine (L-NMMA). Treatment with a bolus dose of 4-ABH4 at 2 h after LPS challenge significantly improved the 6-day survival rate, compared with the controls treated with saline. L-NMMA treatment did not significantly influence the survival rate. This bolus treatment, using either compound, had no effect on the plasma nitrite + nitrate or plasma IL-6 levels. The continuous infusion of 4-ABH4 efficiently suppressed the enhanced calcium-dependent/independent NO synthase activities induced by endotoxin in lung homogenates and completely suppressed the increase in plasma nitrite + nitrate caused by endotoxin at 5 h, with no significant difference compared with the L- NMMA treatment. Treatment of RAW264.7 murine macrophages with 4-ABH4 but not with L-NMMA suppressed endotoxin-induced tumor necrosis factor-α release by the cells, whereas nitrite in the supernatant decreased in a dose-dependent fashion in both assay systems. Our data show that 4-ABH4, an inhibitor of inducible NO synthase, significantly improves survival in a rat model of endotoxic shock when administered in a bolus dose that does not reduce plasma total nitrite + nitrate levels. Because we observed no overt signs of toxicity and no influence on organ-specific tetrahydrobiopterin levels, we conclude that the novel compound 4-ABH4 is a promising drug candidate for protection against endotoxin-related mortality.

Received 20 Jul 1999; first review completed 30 Aug 1999; accepted in final form 18 Nov 1999

Address reprint requests to Soheyl Bahrami, PhD, Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Donaueschingenstraβe 13, A-1200 Vienna, Austria.

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