title: Chronic oral supplementation with sepiapterin prevents endothelial dysfunction and oxidative stress in small mesenteric arteries from diabetic (db/db) mice.
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.
authors.affiliation: Smooth Muscle Research Group, The University of Calgary, Alberta, Canada.
authors.forename: Malarvannan
authors.initials: M
authors.lastname: Pannirselvam
authors.forename: Valerie
authors.initials: V
authors.lastname: Simon
authors.forename: Subodh
authors.initials: S
authors.lastname: Verma
authors.forename: Todd
authors.initials: T
authors.lastname: Anderson
authors.forename: Chris R
authors.initials: CR
authors.lastname: Triggle
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D001708:Biopterins / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000737:chemistry; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology; D006136:GTP Cyclohydrolase / Q000737:chemistry / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D017537:Mesenteric Artery, Inferior / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL / Q000378:metabolism; D019798:Neopterin / Q000737:chemistry / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D010656:Phenylephrine / Q000494:pharmacology; D011622:Pterins / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D011622:Pterins; D010656:Phenylephrine; D001708:Biopterins; D008315:Malondialdehyde; D019798:Neopterin; C017226:7,8-dihydrobiopterin; C016727:sepiapterin; D006136:GTP Cyclohydrolase; C003402:sapropterin; D000109:Acetylcholine