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

Malarvannan Pannirselvam, Valerie Simon, Subodh Verma, Todd Anderson, Christopher Triggle

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1. We previously reported that acute incubation with tetrahydrobiopterin (BH 4) or sepiapterin, a cofactor for endothelial nitric oxide synthase and a stable precursor of BH 4, 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 kg -1 day -1) to db/db mice on endothelium function, biopterin levels and lipid peroxidation in SMA. 2. 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. 3. BH 4 levels and guanosine triphosphate cyclohydrolase I activity in SMA were similar in db/+ and db/db mice. Sepiapterin treatment had no effects on BH 4 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. 4. Thiobarbituric acid reactive substance, malondialdehyde, a marker of lipid peroxidation, was higher in SMA from db/db mice, and was normalized by sepiapterin treatment. 5. 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 BH 4 may not be the basis for endothelial dysfunction in SMA from db/db mice.

Original languageEnglish
Pages (from-to)701-706
Number of pages6
JournalBritish Journal of Pharmacology
Issue number4
Publication statusPublished - Oct 2003
Externally publishedYes



  • db/db mice
  • Endothelial dysfunction
  • Oxidative stress
  • Sepiapterin
  • Tetrahydrobiopterin
  • Type II diabetes

ASJC Scopus subject areas

  • Pharmacology

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