title: Microvascular dysfunction after transient high glucose is caused by superoxide-dependent reduction in the bioavailability of NO and BH(4).
abstract: We hypothesized that transient high-glucose concentration interferes with mediation by nitric oxide (NO) of flow-induced dilation (FID) of arterioles due to enhanced production of superoxide. In isolated, pressurized (80 mmHg) rat gracilis muscle arterioles ( approximately 130 microm) after transient high-glucose treatment (tHG; incubation with 30 mM glucose for 1 h), FID was reduced (maximum: control, 38 +/- 4%; after tHG, 17 +/- 3%), which was not further diminished by the NO synthase (NOS) inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME; 18 +/- 2%). Correspondingly, an enhanced polyethylene-glycol-SOD (PEG-SOD)-sensitive superoxide production was detected after tHG in carotid arteries by dihydroethydine (DHE) staining. Presence of PEG-SOD during tHG prevented the reduction of FID (41 +/- 3%), which could be inhibited by l-NAME (20 +/- 4%). Administration of PEG-SOD after tHG did not prevent the reduction of FID (22 +/- 3%). Sepiapterin, a precursor of the NO synthase cofactor tetrahydrobiopterin (BH(4)), administered during tHG did not prevent the reduction of FID (maximum, 15 +/- 5%); however, it restored FID when administered after tHG (32 +/- 4%). Furthermore, inhibition of either glycolysis by 2-deoxyglucose or mitochondrial complex II by 2-thenoyltrifluoroacetone reduced the tHG-induced DHE-detectable enhanced superoxide production in carotid arteries and prevented FID reduction in arterioles (39 +/- 5 and 35 +/- 2%). Collectively, these findings suggest that in skeletal muscle arterioles, a transient elevation of glucose via its increased metabolism, elicits enhanced production of superoxide, which decreases the bioavailability of NO and the level of the NOS cofactor BH(4), resulting in a reduction of FID mediated by NO.
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, NY 10595, USA.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Bagi
authors.forename: Erika
authors.initials: E
authors.lastname: Toth
authors.forename: Akos
authors.initials: A
authors.lastname: Koller
authors.forename: Gabor
authors.initials: G
authors.lastname: Kaley
mesh_terms: D000818:Animals; D001160:Arterioles / Q000503:physiopathology*; D001682:Biological Availability; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism; D002339:Carotid Arteries / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004996:Ethidium; D005947:Glucose / Q000008:administration & dosage*; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply; D009569:Nitric Oxide / Q000378:metabolism; D011312:Pressure; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000502:physiology; D013481:Superoxides / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D007202:Indicators and Reagents; D013481:Superoxides; D001708:Biopterins; D009569:Nitric Oxide; C003402:sapropterin; D004996:Ethidium; D005947:Glucose