Chronic oral supplementation with sepiapterin prevents endothelial dysfunction and oxidative stress in small mesenteric arteries from diabetic (db/db) mice

Br J Pharmacol. 2003 Oct;140(4):701-6. doi: 10.1038/sj.bjp.0705476.

Abstract

We previously reported that acute incubation with tetrahydrobiopterin (BH4) or sepiapterin, a cofactor for endothelial nitric oxide synthase and a stable precursor of BH4, respectively, enhanced the acetylcholine (Ach)-induced relaxation of isolated small mesenteric arteries (SMA) from diabetic (db/db) mice. In this study, we investigated the effect of chronic oral supplementation of sepiapterin (10 mg x kg-1 x day-1) to db/db mice on endothelium function, biopterin levels and lipid peroxidation in SMA. Oral dietary supplementation with sepiapterin had no effect on glucose, triglyceride, cholesterol levels and body weight. SMA from db/db mice showed enhanced vascular reactivity to phenylephrine, which was corrected with sepiapterin supplementation. Furthermore, Ach, but not sodium nitroprusside-induced relaxation, was improved with sepiapterin supplementation in db/db mice. BH4 levels and guanosine triphosphate cyclohydrolase I activity in SMA were similar in db/+ and db/db mice. Sepiapterin treatment had no effects on BH4 or guanosine triphosphate cyclohydrolase I activity. However, the level of dihydrobiopterin+biopterin was higher in SMA from db/db mice, which was corrected following sepiapterin treatment. Thiobarbituric acid reactive substance, malondialdehyde, a marker of lipid peroxidation, was higher in SMA from db/db mice, and was normalized by sepiapterin treatment. These results indicate that sepiapterin improves endothelial dysfunction in SMA from db/db mice by reducing oxidative stress. Furthermore, these results suggest that decreased biosynthesis of BH4 may not be the basis for endothelial dysfunction in SMA from db/db mice.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / pharmacology
  • Administration, Oral*
  • Animals
  • Biopterin / adverse effects
  • Biopterin / analogs & derivatives*
  • Biopterin / biosynthesis
  • Biopterin / chemistry
  • Diabetes Mellitus / drug therapy*
  • Diabetes Mellitus / physiopathology
  • Disease Models, Animal
  • Drug Administration Schedule
  • Drug Therapy, Combination
  • Endothelium, Vascular / chemistry
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / physiology
  • GTP Cyclohydrolase / chemistry
  • GTP Cyclohydrolase / metabolism
  • Lipid Peroxidation / drug effects
  • Lipid Peroxidation / physiology
  • Male
  • Malondialdehyde / blood
  • Mesenteric Artery, Inferior / chemistry
  • Mesenteric Artery, Inferior / drug effects*
  • Mesenteric Artery, Inferior / physiology
  • Mice
  • Mice, Inbred C57BL / metabolism
  • Neopterin / chemistry
  • Neopterin / metabolism
  • Oxidative Stress / drug effects*
  • Oxidative Stress / physiology
  • Phenylephrine / pharmacology
  • Pterins / administration & dosage*
  • Pterins / pharmacokinetics
  • Pterins / therapeutic use
  • Vasoconstriction / drug effects
  • Vasoconstriction / physiology
  • Vasodilation / drug effects
  • Vasodilation / physiology

Substances

  • Pterins
  • Phenylephrine
  • Biopterin
  • Malondialdehyde
  • Neopterin
  • 7,8-dihydrobiopterin
  • sepiapterin
  • GTP Cyclohydrolase
  • sapropterin
  • Acetylcholine