Effects of tetrahydrobiopterin on nitric oxide bioavailability and renal hemodynamics in healthy volunteers.
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.
Artunc
Ferruh
F
Department of Internal Medicine, University Hospital of Tuebingen, Tuebingen - Germany. ferruh.artunc@med.uni-tuebingen.de
Essig
Michael
M
Artunc
Nilguen
N
Plachtzik
Claudia
C
Reich
Michael
M
Boehmer
Gabriele
G
Haering
Hans-Ulrich
HU
Erley
Christiane M
CM
Risler
Teut
T
D000284:Administration, Oral; D000328:Adult; D001708:Biopterins / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006152:Cyclic GMP / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D012016:Reference Values; D012079:Renal Circulation / Q000187:drug effects* / Q000502:physiology; D017595:Renal Plasma Flow / Q000187:drug effects* / Q000502:physiology
D001708:Biopterins; D009569:Nitric Oxide; C003402:sapropterin; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester