Inhalation of the nitric oxide synthase cofactor tetrahydrobiopterin in healthy volunteers.
Pulmonary endothelial dysfunction is the hallmark of acute lung injury. Impaired pulmonary endothelial nitric oxide (NO) production in this event has been described. Tetrahydrobiopterin (BH4) is an essential cofactor for NO synthase and modulator of its activity. At high local concentrations, BH4 provokes local vasodilation in vivo in healthy individuals. At lower concentrations, BH4 selectively and locally restores disturbed NO-dependent vasodilation in patients with endothelial dysfunction. In this preliminary study, we therefore investigated the feasibility of BH4 inhalation in five healthy human volunteers. Inhalation of buffered, aqueous BH4-dihydrochloride solution was well tolerated; despite the buffer, BH4 stability was completely preserved. Resorption of inhaled BH4 was demonstrated by significantly increased BH4 levels in plasma and urine. Inhaled BH4 did not alter pulmonary function and had no effect on systemic hemodynamic values. Our data demonstrate that inhalation is a novel method for local BH4 administration, offering a basic therapeutic tool for investigation of restoration of impaired NO-dependent vasodilation due to pulmonary endothelial dysfunction.
Walter
R
R
Department of Medicine, University Hospital, Zürich, Switzerland.
Blau
N
N
Schaffner
A
A
Schneemann
M
M
Speich
R
R
Stocker
R
R
Naujeck
B
B
Schoedon
G
G
D000280:Administration, Inhalation; D000328:Adult; D001708:Biopterins / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D001794:Blood Pressure / Q000187:drug effects; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D010865:Pilot Projects; D011622:Pterins / Q000652:urine; D015656:Respiratory Mechanics / Q000187:drug effects; D014976:Xanthopterin / Q000652:urine
D011622:Pterins; D001708:Biopterins; C008217:isoxanthopterin; D019001:Nitric Oxide Synthase; C003402:sapropterin; D014976:Xanthopterin