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

H. Kinoshita, S. Milstien, C. Wambi, Zvonimir S Katusic

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59 Citations (Scopus)

Abstract

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 ionophore 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, 2VG-nitro-Larginine methyl ester (10~4 M), abolished relaxations to bradykinin or A23187 in control arteries and in DAHPtreated arteries. These studies demonstrate that in cerebral arteries, decreased intracellular levels of tetrahydrobiopterin can reduce endothelium-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)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume42
Issue number2
StatePublished - 1997

Fingerprint

Basilar Artery
Endothelium
Canidae
Arteries
Calcimycin
Bradykinin
Cerebral Arteries
Superoxide Dismutase
GTP Cyclohydrolase
Cyclooxygenase Inhibitors
Nitric Oxide Donors
Calcium Ionophores
Nitric Oxide Synthase Type III
sapropterin
Nitric Oxide Synthase
Superoxides
Indomethacin
Blood Vessels
Nitric Oxide
Esters

Keywords

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

ASJC Scopus subject areas

  • Physiology

Cite this

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title = "Inhibition of tetrahydrobiopterin biosynthesis impairs endothelium-dependent relaxations in canine basilar artery",
abstract = "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 ionophore 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, 2VG-nitro-Larginine methyl ester (10~4 M), abolished relaxations to bradykinin or A23187 in control arteries and in DAHPtreated arteries. These studies demonstrate that in cerebral arteries, decreased intracellular levels of tetrahydrobiopterin can reduce endothelium-dependent relaxations. Production of Superoxide anions during activation of dysfunctional endothelial nitric oxide synthase appears to be responsible for the impairment of endothelial function.",
keywords = "Cerebral artery, Nitric oxide, Receptors, Sepiapterin, Superoxide anions",
author = "H. Kinoshita and S. Milstien and C. Wambi and Katusic, {Zvonimir S}",
year = "1997",
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T1 - Inhibition of tetrahydrobiopterin biosynthesis impairs endothelium-dependent relaxations in canine basilar artery

AU - Kinoshita, H.

AU - Milstien, S.

AU - Wambi, C.

AU - Katusic, Zvonimir S

PY - 1997

Y1 - 1997

N2 - 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 ionophore 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, 2VG-nitro-Larginine methyl ester (10~4 M), abolished relaxations to bradykinin or A23187 in control arteries and in DAHPtreated arteries. These studies demonstrate that in cerebral arteries, decreased intracellular levels of tetrahydrobiopterin can reduce endothelium-dependent relaxations. Production of Superoxide anions during activation of dysfunctional endothelial nitric oxide synthase appears to be responsible for the impairment of endothelial function.

AB - 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 ionophore 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, 2VG-nitro-Larginine methyl ester (10~4 M), abolished relaxations to bradykinin or A23187 in control arteries and in DAHPtreated arteries. These studies demonstrate that in cerebral arteries, decreased intracellular levels of tetrahydrobiopterin can reduce endothelium-dependent relaxations. Production of Superoxide anions during activation of dysfunctional endothelial nitric oxide synthase appears to be responsible for the impairment of endothelial function.

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KW - Nitric oxide

KW - Receptors

KW - Sepiapterin

KW - Superoxide anions

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