Contribution of polyol pathway to arteriolar dysfunction in hyperglycemia. Role of oxidative stress, reduced NO, and enhanced PGH2/TXA2 mediation

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 (PGH2/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 ox...