Microvascular dysfunction after transient high glucose is caused by superoxide-dependent reduction in the bioavailability of NO and BH4

Zsolt Bagi, Erika Toth, Akos Koller, Gabor Kaley

Research output: Contribution to journalArticle

44 Scopus citations

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 (∼130 μm) 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 Nω-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 (BH4), 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.

Original languageEnglish (US)
Pages (from-to)H626-H633
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume287
Issue number2 56-2
DOIs
StatePublished - Aug 1 2004
Externally publishedYes

Keywords

  • 2-deoxyglucose
  • Arteriole
  • Glycolysis
  • Mitochondrial complex II

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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