Effect of tetrahydrobiopterin on endothelial function in canine middle cerebral arteries

Masato Tsutsui, Sheldon Milstien, Zvonimir S. Katusic

Research output: Contribution to journalArticlepeer-review

79 Scopus citations


Tetrahydrobiopterin is an essential cofactor required for activation of NO synthase. However, in intact arteries, the exact role of tetrahydrobiopterin in the regulation of NO synthase activity is not fully understood. The present study was de signed to determine the effect of increasing intracellular tetrahydrobiopterin levels on endothelial function in isolated canine middle cerebral arteries. The arterial segments were incubated in MEM for 24 hours at 37°C in the presence or absence of a tetrahydrobiopterin precursor, sepiapterin (10-4 mol/L), and/or superoxide dismutase (150 U/mL). The rings were suspended for isometric tension recording. Tetrahydrobiopterin levels were assayed by high-performance liquid chromatography. Production of cGMP was measured by radioimmunoassay. Incubation with sepiapterin markedly increased intracellular tetrahydrobiopterin levels. In sepiapterin treated arteries, endothelium- dependent relaxations to calcium ionophore A23187 and intracellular cGMP levels were significantly reduced. Superoxide dismutase alone did not affect either relaxation to A23187 or production of cGMP. However, when arteries were incubated with superoxide dismutase plus sepiapterin, endothelium- dependent relaxations to A23187, as well as cGMP production, were significantly augmented. The augmentation of cGMP was observed in rings with (but not without) endothelium. Incubation of arteries in calcium free medium almost abolished the synergistic effect of tetrahydrobiopterin and superoxide dismutase on cGMP production. These results demonstrate that increased availability of tetrahydrobiopterin may activate endothelial NO synthase. This effect appears to be critically dependent on the presence of superoxide dismutase.

Original languageEnglish (US)
Pages (from-to)336-342
Number of pages7
JournalCirculation research
Issue number2
StatePublished - Jan 1 1996


  • NO
  • NO synthase
  • superoxide anion
  • superoxide dismutase

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine


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