Glucocorticoids inhibit tetrahydrobiopterin-dependent endothelial function

Tetrahydrobiopterin (BH4) acts as an important co-factor for endothelial ni tric oxide synthase (eNOS). Glucocorticoids have been shown to inhibit expr ession of the rate-limiting enzyme for tetrahydrobiopterin synthesis, GTP c yclohydrolase, in other cell types. We hypothesized that endothelium-depend ent vasodilator responses would be blunted in rats made hypertensive with d examethasone. Further, we hypothesized that treatment of rat vascular segme nts with dexamethasone would result in attenuation of endothelial function accompanied by decreased GTP cyclohydrolase expression. We report that endo thelium-dependent relaxation responses to the calcium ionophore A23187 are reduced in aortic rings from dexamethasone-hypertensive rats compared with sham values, Dexamethasone incubation abolishes contraction to N-omega-nitr o-L-arginine (L-NNA, 10(-5)M) in endothelium-intact aortic rings, and inhib its expression of GTP cyclohydrolase. We conclude that inhibition of BH4 sy nthesis by glucocorticoid regulation of GTP cyclohydrolase expression may c ontribute to reduced endothelium-dependent vasodilation characteristic of g Iucocorticoid-induced hypertension.