Inhibition of tetrahydrobiopterin biosynthesis impairs endothelium- dependent relaxations in canine basilar artery

H. Kinoshita, S. Milstien, G. Wambi, Z. S. Katusic

Research output: Contribution to journalArticlepeer-review

59 Scopus citations


Tetrahydrobiopterin is an essential cofactor in biosynthesis of nitric oxide. The present study was designed to determine the effect of decreased intracellular tetrahydrobiopterin levels on endothelial function of isolated cerebral arteries. Blood vessels were incubated for 6 h in minimum essential medium (MEM) in the presence or absence of a GTP cyclohydrolase I inhibitor, 2,4-diamino-6-hydroxypyrimidine (DAHP, 10-2 M). Rings with and without endothelium were suspended for isometric force recording in the presence of a cyclooxygenase inhibitor, indomethacin (10-5 M). In arteries with endothelium, DAHP significantly reduced intracellular levels of tetrahydrobiopterin. DAHP in combination with a precursor of the salvage pathway of tetrahydrobiopterin biosynthesis, sepiapterin (10-4 M), not only restored but increased levels of tetrahydrobiopterin above control values. In DAHP-treated arteries, endothelium-dependent relaxations to bradykinin (10- 10-10-6 M) or calcium ionophere A23187 (10-9-10-6 M) were significantly reduced, whereas endothelium-independent relaxations to a nitric oxide donor, 3-morpholinosydnonimine (10-9-10-4 M), were not affected. When DAHP-treated arteries with endothelium were incubated with sepiapterin (10-4 M) or superoxide dismutase (150 U/ml), relaxations to bradykinin and A23187 were restored to control levels. In contrast, superoxide dismutase did not affect endothelium-dependent relaxations in arteries incubated in MEM. A nitric oxide synthase inhibitor, N(G)-nitro-L- arginine methyl ester (10-4 M), abolished relaxations to bradykinin or A23187 in control arteries and in DAHP-treated arteries. These studies demonstrate that in cerebral arteries, decreased intracellular levels of tetrahydrobiopterin can reduce endethelium-dependent relaxations. Production of superoxide anions during activation of dysfunctional endothelial nitric oxide synthase appears to be responsible for the impairment of endothelial function.

Original languageEnglish (US)
Pages (from-to)H718-H724
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Issue number2 42-2
StatePublished - 1997


  • Cerebral artery
  • Nitric oxide
  • Receptors
  • Sepiapterin
  • Superoxide anions

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


Dive into the research topics of 'Inhibition of tetrahydrobiopterin biosynthesis impairs endothelium- dependent relaxations in canine basilar artery'. Together they form a unique fingerprint.

Cite this