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

Authors

  • Malarvannan Pannirselvam,

    1. Smooth Muscle Research Group, The University of Calgary, Alberta, Canada
    2. Department of Pharmacology & Therapeutics, The University of Calgary, Alberta T2N 4N1, Canada
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  • Valerie Simon,

    1. Calgary Laboratory Services, The University of Calgary, Alberta, Canada
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  • Subodh Verma,

    1. Toronto General Hospital, Toronto, Canada
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  • Todd Anderson,

    1. Division of Cardiology, Faculty of Medicine, The University of Calgary, Alberta, Canada
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  • Chris R Triggle

    Corresponding author
    1. Smooth Muscle Research Group, The University of Calgary, Alberta, Canada
    2. Department of Pharmacology & Therapeutics, The University of Calgary, Alberta T2N 4N1, Canada
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    • 6

      Current address: Department of Pharmacology & Therapeutics, 3330, Hospital Drive (N.W.), Calgary, Alberta, Canada T2N 4N1


Smooth Muscle Research Group, The University of Calgary, Alberta, Canada. E-mail: triggle@ucalgary.ca

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 kg−1 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.

British Journal of Pharmacology (2003) 140, 701–706. doi:10.1038/sj.bjp.0705476

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