Tetrahydrobiopterin as another EDRF in man.

Endotoxin and inflammatory cytokines downregulate expression of constitutive nitric oxide synthase (cNOS) in human vascular endothelial cells with concomitant increase of tetrahydrobiopterin synthesis in these cells and parallel upregulation of inducible NOS expression in smooth muscle cells, indicating compartmentalized nitric oxide (NO) production under septic conditions in man. In this report the compartmentalization has been further studied using dual chamber cell cultures with inflammatory activated human endothelial cells. We show that endothelial cells secrete BH4 vectorially into the basal direction thereby providing underlining smooth muscle cells with the cofactor necessary for NO production. Furthermore, by laser Doppler velocimetry we show that intraarterial infusion of BH4 induces strong vasodilatation in man. Consumption of L-arginine and production of cyclic GMP increased and therefore imply NO as second messenger. Thus the discovery of an endothelium-derived factor regulating NOS activity would reconcile the concept of an inflammatory EDRF that is not NO itself but results in NO-dependent vasodilatation in man.