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Inhibitors of aldose reductase and sorbitol dehydrogenase mitigate hyperglycemia‐induced arteriolar dysfunction
Author(s) -
Veres Zoltan,
Koller Akos
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.594.5
Subject(s) - polyol pathway , aldose reductase , sorbitol dehydrogenase , sorbitol , fructose , medicine , endocrinology , nitric oxide , chemistry , oxidative stress , diabetes mellitus , biochemistry , biology
Hyperglycemia by activating the polyol pathway elicits increases in intracellular sorbitol and fructose concentrations. Previously we showed that in isolated arterioles administration of sorbitol (10 −7 M) elicited oxidative stress, which interferes with nitric oxide (NO) bioavailability and thus dilations. We hypothesized that an elevated level of fructose also contributes to the development of hyperglycemia‐induced dysfunction of microvessels. In isolated rat gracilis muscle arterioles (~150 μm at 80mmHg), high glucose treatment (25 mM for 30 min) reduced flow dependent dilation (max: 39 ±2 vs. 15 ±1 %), which was significantly reversed by an aldose reductase inhibitor, zopolrestat (max: 27±2 %) and partially by a sorbitol dehydrogenase inhibitor (SDI), CP‐470,711 (max: 23±3 %). Also, SDI ‐ in part ‐ restored dilations to flow in the presence of elevated sorbitol. Incubation of arterioles with fructose (10 −4 M) reduced flow dependent dilations (max: 39±2 vs. 12±2 %), which were not further affected by inhibition of NO synthase by L‐NAME, but were partially reversed by SOD/CAT and PGH2/TXA2 receptor blocker SQ‐29548. Thus, we suggest that hyperglycemia ‐ by elevating intracellular sorbitol and fructose levels ‐ induces oxidative stress, which interferes with NO‐mediated dilations and promotes PGH2/TXA2 release. Thus the polyol pathway may contribute to the development of microvascular dysfunction in diabetes mellitus. (Grants: Hungarian SRF/OTKA T48376, K71591; HSC/ETT 364/2006 and AHA F. Aff. 0855910D, USA)