Toth Erika, Racz Anita, Toth Janos, Kaminski Pawel M, Wolin Michael S, Bagi Zsolt, Koller Akos
Department of Physiology, Semmelweis University, Budapest, Hungary.
Am J Physiol Heart Circ Physiol. 2007 Nov;293(5):H3096-104. doi: 10.1152/ajpheart.01335.2006. Epub 2007 Sep 14.
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.
高血糖通过多元醇途径增加葡萄糖代谢，这会导致细胞内山梨醇浓度升高。因此，我们推测山梨醇水平升高会促使高血糖诱导的微血管功能障碍的发生。在分离的、加压（80 mmHg）的大鼠股薄肌小动脉（约150微米）中，高糖处理（25 mM）导致流量依赖性舒张功能降低（从最大值39±2%降至15±1%），而醛糖还原酶抑制剂佐泊司他可显著减轻这种降低（最大值为27±2%）。递增剂量的山梨醇（10⁻¹⁰ - 10⁻⁴ M）引起剂量依赖性收缩（最大值为22±3%），去除内皮、前列腺素H₂/血栓素A₂（PGH₂/TXA₂）受体（TP）拮抗剂SQ - 29548或超氧化物歧化酶（SOD）加过氧化氢酶（CAT）可消除这种收缩。用山梨醇（10⁻⁷ M）孵育小动脉会降低流量依赖性舒张功能（从最大值39±2%降至20±1.5%），N⁻硝基 - L - 精氨酸甲酯抑制一氧化氮合酶对此无进一步影响，但SOD加CAT可预防，SQ - 29548可减轻。一氧化氮供体硝普钠诱导的（10⁻⁹ - 10⁻⁶ M）舒张也以SQ - 29548和SOD加CAT可逆的方式降低，而腺苷诱导的舒张不受山梨醇暴露的影响。山梨醇通过腔肠素增强的化学发光检测到显著增加动脉超氧化物的产生，SOD加CAT可抑制这种产生。山梨醇处理还增加了动脉3 - 硝基酪氨酸的形成。我们认为，高血糖通过升高细胞内山梨醇诱导氧化应激，这会干扰一氧化氮的生物利用度并促进PGH₂/TXA₂释放，二者均影响小动脉血管舒缩反应的调节。因此，多元醇途径活性增加可能有助于糖尿病微血管功能障碍的发生。
