EFFECTS OF ACTIVATING AND DEACTIVATING CYTOKINES ON THE FUNCTIONALLY LINKED TETRAHYDROBIOPTERIN NO PATHWAYS IN VASCULAR SMOOTH-MUSCLE CELLS

The functional relationship of nitric oxide (NO) production and synthe sis of tetrahydrobiopterin (BH4), the requisite cofactor for NO syntha se, was investigated in rat aortic smooth muscle cells (SMC). Inflamma tory cytokines induced BH4 and NO synthesis in different ratios, IL-1 beta induced mainly NO synthesis with concomitant but limiting amounts of BH4 for maximal NO production. TNF alpha did not induce NO synthes is but induced BH4 synthesis. IFN gamma was ineffective on both the in duction of NO and BH4 synthesis. TGF beta downregulated NO production but did not affect BH4 biosynthesis. IL-4 and IL-10 had no effect on b oth BH4 and NO synthesis. Activating cytokines strongly synergized in induction of NO production, whereas endogenous BH4 production became i nsufficient for maximal NO synthesis. Exogenous cofactor in the form o f sepiapterin or authentic BH4, but not the natural isomer 7-BH4, enha nced NO production twofold. Inhibition of BH4 synthesis with dicumarol abolished NO production that could be restored in the presence of BH4 . Copyright (C) 1996 Elsevier Science B.V.