NITRIC-OXIDE PRODUCTION DEPENDS ON PRECEDING TETRAHYDROBIOPTERIN SYNTHESIS BY ENDOTHELIAL-CELLS - SELECTIVE SUPPRESSION OF INDUCED NITRIC-OXIDE PRODUCTION BY SEPIAPTERIN REDUCTASE INHIBITORS

Using murine vascular endothelial cells expressing both constitutive a nd inducible nitric oxide synthases (cNOS and iNOS), we explored the f easibility of suppressing cytokine-induced nitric oxide (NO) productio n without affecting constitutive NO production by inhibition of the te trahydrobiopterin (BH4) biosynthesis. We show in this study that in en dothelial cells cytokine/endotoxin-activated BH4 synthesis precedes th e induction of NO generation. Using the sepiapterin reductase inhibito rs phenprocoumon or dicumarol as BH4 synthesis inhibitors, we achieved a pronounced and selective suppression of induced NO production in cy tokine-activated endothelial cells. Addition of exogenous BH4, but not sepiapterin, restored NO production in the presence of the inhibitors . Despite profound inhibition of the BH4 biosynthesis, constitutive NO synthesis was not affected, thereby demonstrating the selectivity and specificity of the inhibitors. Suppression of enhanced NO production by sepiapterin reductase inhibitors such as cumaroles could provide ph armacologic means for therapeutic interventions in NO-mediated pathoph ysiologic events. (C) 1994 Academic Press, Inc.