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

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 (approximately 150 microm), 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 H(2)/thromboxane A(2) (PGH(2)/TXA(2)) 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 N(omega)-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 PGH(2)/TXA(2) 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.

Ferulic acid, a natural polyphenol, alleviates insulin resistance and hypertension in fructose fed rats: Effect on endothelial-dependent relaxation

“…This is in accordance with the reported restoration of NO production by AR inhibition in human umbilical endothelial cells cultured in a medium with high glucose content [40]. These assumptions are also supported by previous work in which ZOP inhibited the reduction in flow-induced dilation induced by high glucose [36] and restored NO production in ischemic myocardial injury [41]. In addition, FER improved the bioavailability of stimulated NO in the aortas isolated from spontaneously hypertensive rats [42].…”

“…Our data indicated that both FER and ZOP significantly prevented the diminished relaxation to ACh in aortas isolated from animals with MetS without affecting the response to PE. This coincides with pprevious reports in which zopolrestat recover the high glucose-induced reduction of flow-induced dilation [36]. On the other hand, short-term in vitro incubation of aortas isolated from (+ 10% fructose) animals with FER and ZOP restored normal endothelial dependent relaxation.…”

Insulin resistance and impaired functional vasodilation in obese Zucker rats

“…5 and 6). A recently study (49) showed that increased endothelial sorbitol is a possible mechanism for the hyperglycemia-induced ROS and the resultant enhanced TP activation, resulting in impaired flow-mediated dilation. In addition, rosiglitazone treatment decreased NADPH oxidase activity but failed to complete restore superoxide levels, suggesting the possibility of other NADPH oxidase-independent ROS, which may account for the remained impairment in functional dilation after treatment in OZRs.…”

Cardiac Effects of HDL and Its Components on Diabetic Cardiomyopathy

“…Inhibition of the polyol pathway improves the function of SERCA and ryanodine receptor by protecting them from irreversible oxidation [67]. Besides the importance of aldose reductase in cardiac dysfunction under diabetes mellitus, aldose reductase has been implicated in the development of microvascular dysfunction during diabetes [68]. Inhibition of aldose reductase prevents protein kinase C and nuclear factor-κB activation induced by a variety of stimuli such as TNF-α, fibroblast growth factor-2, angiotensin II, and high glucose [69][70][71], suggesting that aldose reductase regulates stress responses and the activation of nuclear factor-κB and other protein kinase C-sensitive transcription factors.…”