ABSTRACT
BACKGROUND: The endothelial nitric oxide (NO) system plays a central role in regulating vascular tone. Endothelial dysfunction has been closely linked to reduced activity in the NO system. Tetrahydrobiopterin (BH4) is an essential cofactor of all NO synthase isoforms. METHODS: We examined the effects of BH4 on the NO system assessed by measurement of serum cGMP levels and NO breakdown products (NOx) in 12 healthy volunteers. RESULTS: Application of a total of 19 mg/kg BH4 intravenously (i.v.) over 3 hours led to a dose-dependent increase in serum cGMP concentrations from a median 3.3 nM (interquartile range [IQR] 1.1-5.6) to 5.7 nM (IQR 2.4-13.3, p=0.008) and NOx from a median 49.3 microM (IQR 39.8-56.6) to 59.7 microM (39.6-85.5) (p=0.058). Systemic and renal hemodynamics measured by inulin and p-aminohippuric acid (PAH) clearance remained unchanged. Plasma renin activity was significantly increased (2.0 [IQR 1.0-2.8] to 2.3 ng AngI/mL per hour [IQR 1.7-4.0], p=0.045), whereas aldosterone, erythropoietin and B-type natriuretic peptide levels did not change. In a second study, oral BH4 given over 3 days (800 mg/day) similarly increased serum cGMP and ameliorated the depressive effects of the NO synthase inhibitor L-NAME (1.5 mg/kg i.v.) on the glomerular filtration rate. CONCLUSIONS: Application of BH4 in high doses is safe and enhances formation of cGMP, pointing to increased bioavailability of NO.
Subject(s)
Biopterins/analogs & derivatives , Nitric Oxide/metabolism , Renal Circulation/drug effects , Renal Plasma Flow/drug effects , Administration, Oral , Adult , Biopterins/administration & dosage , Biopterins/pharmacokinetics , Cyclic GMP/blood , Dose-Response Relationship, Drug , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Glomerular Filtration Rate/drug effects , Glomerular Filtration Rate/physiology , Humans , Infusions, Intravenous , Male , NG-Nitroarginine Methyl Ester/administration & dosage , NG-Nitroarginine Methyl Ester/pharmacology , Reference Values , Renal Circulation/physiology , Renal Plasma Flow/physiologyABSTRACT
Layers of niobium clusters that are linked to each other through zigzag chains of edge-sharing [TiCl4 O2 ] ocatahedra are the central structural features of the title compound. Bridging of the chains by [(Nb6 Cl8i O4i )Cl6a ]6- clusters results in the formation of empty tunnels (a section of the structure is shown on the right).