title: Tetrahydrobiopterin rescues impaired responses of cerebral resistance arterioles during type 1 diabetes.
abstract: Our goal was to test the hypothesis that administration of tetrahydrobiopterin (BH4) would improve impaired endothelial nitric oxide synthase-dependent dilation of cerebral arterioles during type 1 diabetes. In addition, we examined the influence of BH4on levels of superoxide in brain tissue. In vivo diameter of cerebral arterioles in nondiabetic and diabetic rats was measured in response to endothelial nitric oxide synthase-dependent agonists (acetylcholine and adenosine 5'-diphosphate) and an endothelial nitric oxide synthase-independent agonist (nitroglycerine) before and during application of BH4(1.0 µM). We also measured levels of superoxide from cortex tissue in nondiabetic and diabetic rats under basal states and during BH4Acetylcholine and adenosine 5'-diphosphate dilated cerebral arterioles in nondiabetic rats, but this vasodilation was significantly impaired in diabetic rats. In contrast, nitroglycerine produced similar vasodilation in nondiabetic and diabetic rats. Application of BH4did not enhance vasodilation in nondiabetic rats but improved impaired cerebral vasodilation in diabetic rats. Basal superoxide levels were increased in cortex tissue from diabetic rats, and BH4reduced these levels to that found in nondiabetic rats. Thus, BH4is an important mediator of endothelial nitric oxide synthase-dependent responses of cerebral arterioles in diabetes and may have therapeutic potential for the treatment of cerebral vascular disease.
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD, USA william.mayhan@usd.edu.
authors.forename: William G
authors.initials: WG
authors.lastname: Mayhan
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD, USA.
authors.forename: Denise M
authors.initials: DM
authors.lastname: Arrick
mesh_terms: D000818:Animals; D001160:Arterioles / Q000187:drug effects* / Q000503:physiopathology; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D002561:Cerebrovascular Disorders / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D003925:Diabetic Angiopathies / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010841:Pia Mater / Q000098:blood supply*; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D014665:Vasodilator Agents; D013481:Superoxides; D001708:Biopterins; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; C003402:sapropterin
keywords: Acetylcholine; adenosine 5′-diphosphate; brain; rats; superoxide