Contribution of polyol pathway to arteriolar dysfunction in hyperglycemia. Role of oxidative stress, reduced NO, and enhanced PGH2/TXA 2 mediation

Erika Toth, Anita Racz, Janos Toth, Pawel M. Kaminski, Michael S. Wolin, Zsolt Bagi, Akos Koller

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Hyperglycemia increases glucose metabolism via the polyol pathway, which results in elevations of intracellular sorbitol concentration. Thus we hypothesized that elevated level of sorbitol contributes to the development of hyperglycemia-induced dysfunction of microvessels. In isolated, pressurized (80 mmHg) rat gracilis muscle arterioles (∼150 μm), high glucose treatment (25 mM) induced reduction in flow-dependent dilation (from maximum of 39 ± 2% to 15 ± 1%), which was significantly mitigated by an aldose reductase inhibitor, zopolrestat (maximum 27 ± 2%). Increasing doses of sorbitol (10-10-10-4 M) elicited dose-dependent constrictions (maximum 22 ± 3%), which were abolished by endothelium removal, a prostaglandin H2/thromboxane A2 (PGH 2/TXA2) receptor (TP) antagonist SQ-29548, or superoxide dismutase (SOD) plus catalase (CAT). Incubation of arterioles with sorbitol (10-7 M) reduced flow-dependent dilations (from maximum of 39 ± 2% to 20 ± 1.5%), which was not further affected by inhibition of nitric oxide synthase by Nω-nitro-L-arginine methyl ester but was prevented by SOD plus CAT and mitigated by SQ-29548. Nitric oxide donor sodium nitroprusside-induced (10-9-10-6 M) dilations were also decreased in a SQ-29548 and SOD plus CAT-reversible manner, whereas adenosine dilations were not affected by sorbitol exposure. Sorbitol significantly increased arterial superoxide production detected by lucigenin-enhanced chemiluminescence, which was inhibited by SOD plus CAT. Sorbitol treatment also increased arterial formation of 3-nitrotyrosine. We suggest that hyperglycemia by elevating intracellular sorbitol induces oxidative stress, which interferes with nitric oxide bioavailability and promotes PGH2/TXA2 release, both of which affect regulation of vasomotor responses of arterioles. Thus increased activity of the polyol pathway may contribute to the development of microvascular dysfunction in diabetes mellitus.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume293
Issue number5
DOIs
StatePublished - Nov 1 2007
Externally publishedYes

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Prostaglandin H2
Sorbitol
Hyperglycemia
Oxidative Stress
Catalase
Superoxide Dismutase
Dilatation
Arterioles
Prostaglandin H2 Receptors Thromboxane A2
Glucose
Aldehyde Reductase
Nitric Oxide Donors
polyol
Nitroprusside
Microvessels
Luminescence
Constriction
Nitric Oxide Synthase
Superoxides
Adenosine

Keywords

  • Aldose reductase
  • Flow-dependent dilation
  • Nitric oxide
  • Oxidative stress
  • Prostaglandin H
  • Sorbitol
  • Thromboxane A

ASJC Scopus subject areas

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

Cite this

Contribution of polyol pathway to arteriolar dysfunction in hyperglycemia. Role of oxidative stress, reduced NO, and enhanced PGH2/TXA 2 mediation. / Toth, Erika; Racz, Anita; Toth, Janos; Kaminski, Pawel M.; Wolin, Michael S.; Bagi, Zsolt; Koller, Akos.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 293, No. 5, 01.11.2007.

Research output: Contribution to journalArticle

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abstract = "Hyperglycemia increases glucose metabolism via the polyol pathway, which results in elevations of intracellular sorbitol concentration. Thus we hypothesized that elevated level of sorbitol contributes to the development of hyperglycemia-induced dysfunction of microvessels. In isolated, pressurized (80 mmHg) rat gracilis muscle arterioles (∼150 μm), high glucose treatment (25 mM) induced reduction in flow-dependent dilation (from maximum of 39 ± 2{\%} to 15 ± 1{\%}), which was significantly mitigated by an aldose reductase inhibitor, zopolrestat (maximum 27 ± 2{\%}). Increasing doses of sorbitol (10-10-10-4 M) elicited dose-dependent constrictions (maximum 22 ± 3{\%}), which were abolished by endothelium removal, a prostaglandin H2/thromboxane A2 (PGH 2/TXA2) receptor (TP) antagonist SQ-29548, or superoxide dismutase (SOD) plus catalase (CAT). Incubation of arterioles with sorbitol (10-7 M) reduced flow-dependent dilations (from maximum of 39 ± 2{\%} to 20 ± 1.5{\%}), which was not further affected by inhibition of nitric oxide synthase by Nω-nitro-L-arginine methyl ester but was prevented by SOD plus CAT and mitigated by SQ-29548. Nitric oxide donor sodium nitroprusside-induced (10-9-10-6 M) dilations were also decreased in a SQ-29548 and SOD plus CAT-reversible manner, whereas adenosine dilations were not affected by sorbitol exposure. Sorbitol significantly increased arterial superoxide production detected by lucigenin-enhanced chemiluminescence, which was inhibited by SOD plus CAT. Sorbitol treatment also increased arterial formation of 3-nitrotyrosine. We suggest that hyperglycemia by elevating intracellular sorbitol induces oxidative stress, which interferes with nitric oxide bioavailability and promotes PGH2/TXA2 release, both of which affect regulation of vasomotor responses of arterioles. Thus increased activity of the polyol pathway may contribute to the development of microvascular dysfunction in diabetes mellitus.",
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N2 - Hyperglycemia increases glucose metabolism via the polyol pathway, which results in elevations of intracellular sorbitol concentration. Thus we hypothesized that elevated level of sorbitol contributes to the development of hyperglycemia-induced dysfunction of microvessels. In isolated, pressurized (80 mmHg) rat gracilis muscle arterioles (∼150 μm), high glucose treatment (25 mM) induced reduction in flow-dependent dilation (from maximum of 39 ± 2% to 15 ± 1%), which was significantly mitigated by an aldose reductase inhibitor, zopolrestat (maximum 27 ± 2%). Increasing doses of sorbitol (10-10-10-4 M) elicited dose-dependent constrictions (maximum 22 ± 3%), which were abolished by endothelium removal, a prostaglandin H2/thromboxane A2 (PGH 2/TXA2) receptor (TP) antagonist SQ-29548, or superoxide dismutase (SOD) plus catalase (CAT). Incubation of arterioles with sorbitol (10-7 M) reduced flow-dependent dilations (from maximum of 39 ± 2% to 20 ± 1.5%), which was not further affected by inhibition of nitric oxide synthase by Nω-nitro-L-arginine methyl ester but was prevented by SOD plus CAT and mitigated by SQ-29548. Nitric oxide donor sodium nitroprusside-induced (10-9-10-6 M) dilations were also decreased in a SQ-29548 and SOD plus CAT-reversible manner, whereas adenosine dilations were not affected by sorbitol exposure. Sorbitol significantly increased arterial superoxide production detected by lucigenin-enhanced chemiluminescence, which was inhibited by SOD plus CAT. Sorbitol treatment also increased arterial formation of 3-nitrotyrosine. We suggest that hyperglycemia by elevating intracellular sorbitol induces oxidative stress, which interferes with nitric oxide bioavailability and promotes PGH2/TXA2 release, both of which affect regulation of vasomotor responses of arterioles. Thus increased activity of the polyol pathway may contribute to the development of microvascular dysfunction in diabetes mellitus.

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