Graier W F, Wascher T C, Lackner L, Toplak H, Krejs G J, Kukovetz W R
Institute of Pharmacology and Toxicology, University Graz, Austria.
Diabetes. 1993 Oct;42(10):1497-505. doi: 10.2337/diab.42.10.1497.
The possible role of endothelial dysfunction in early stages of uncomplicated diabetes mellitus was investigated in porcine aortic endothelial cells. Prolonged exposure to various D-glucose concentrations resulted in concentration-dependent amplification of agonist-induced Ca2+ mobilization, whereas L-glucose and D-mannitol failed to mimic the effect of D-glucose. This stimulatory effect of high D-glucose on endothelial Ca2+ mobilization could be antagonized by coincubation with cytochalasin B, which prevented D-glucose uptake into the cells. In agreement with its effect on agonist-induced Ca2+ response, prolonged preincubation with pathological D-glucose concentrations amplified formation of endothelium-derived relaxing factor, which is well established to be strictly attributable to increases in endothelial free Ca2+. In contrast to endothelium-derived relaxing factor formation stimulated by receptor-interacting autacoids, preincubation with high D-glucose failed to modulate A 23,187-induced endothelium-derived relaxing factor formation, which is attributable to unphysiological increases in endothelial free Ca2+ by this ionophore. Similar to its effect on D-glucose-mediated amplification of agonist-stimulated Ca2+ mobilization, cytochalasin B abolished the stimulatory effect of high D-glucose on endothelium-derived relaxing factor formation. We therefore suggest that prolonged exposure to pathological high D-glucose concentrations results in an enhanced endothelium-derived relaxing factor formation caused by amplification of agonist-stimulated Ca2+ mobilization in endothelial cells. This mechanism may be of particular importance representing a possible basis of pathological vasodilation and reduced peripheral resistance in early stages of diabetes mellitus.
在猪主动脉内皮细胞中研究了内皮功能障碍在单纯性糖尿病早期阶段可能发挥的作用。长时间暴露于不同浓度的D-葡萄糖会导致激动剂诱导的Ca2+动员呈浓度依赖性增强，而L-葡萄糖和D-甘露醇则无法模拟D-葡萄糖的作用。高浓度D-葡萄糖对内皮细胞Ca2+动员的这种刺激作用可通过与细胞松弛素B共同孵育来拮抗，细胞松弛素B可阻止D-葡萄糖进入细胞。与其对激动剂诱导的Ca2+反应的影响一致，用病理浓度的D-葡萄糖长时间预孵育会增强内皮衍生舒张因子的形成，而内皮衍生舒张因子的形成已被确认为严格归因于内皮游离Ca2+的增加。与受体相互作用自分泌物质刺激形成的内皮衍生舒张因子不同，高浓度D-葡萄糖预孵育未能调节A 23,187诱导的内皮衍生舒张因子形成，后者是由该离子载体导致内皮游离Ca2+的非生理性增加所致。与它对D-葡萄糖介导的激动剂刺激的Ca2+动员增强作用类似，细胞松弛素B消除了高浓度D-葡萄糖对内皮衍生舒张因子形成的刺激作用。因此，我们认为长时间暴露于病理性高浓度D-葡萄糖会导致内皮衍生舒张因子形成增强，这是由内皮细胞中激动剂刺激的Ca2+动员增强所致。这一机制可能尤为重要，它可能是糖尿病早期病理性血管舒张和外周阻力降低的一个潜在基础。
