Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo, Japan.
J Pharmacol Sci. 2010;112(3):336-42. doi: 10.1254/jphs.09312fp. Epub 2010 Mar 2.
We previously reported that acetylcholine (ACh)-induced vasodilation of retinal arterioles is diminished in diabetic rats; however, the underlying mechanism(s) of this phenomenon has not been fully elucidated. To determine the role of the polyol pathway in the diabetes-induced retinal vascular dysfunction, we investigated the effect of GP-1447, an inhibitor of aldose reductase, on the attenuation of ACh-induced vasodilation of retinal arterioles seen in diabetic rats. Male Wistar rats were treated with streptozotocin (STZ) and experiments were performed 2 weeks later. The STZ-treated animals were given drinking water containing 5% D-glucose to shorten the term for the development of retinal vascular dysfunction. Treatment with GP-1447 was initiated immediately after STZ treatment and continued throughout the 2-week experimental period. The attenuation of retinal vascular responses to ACh were not modified by treatment with GP-1447, whereas the aldose reductase inhibitor completely prevented diabetes-induced thinning of the retina and sorbitol accumulation in the retina and the lens. These results suggest that mechanisms that are independent of the polyol pathway may contribute to the onset of retinal endothelial dysfunction, although the pathway plays an important role in morphological changes of retina and formation of cataracts in diabetic rats.
我们之前曾报道过，糖尿病大鼠的视网膜小动脉在乙酰胆碱（ACh）诱导下的血管舒张作用减弱；然而，这一现象的潜在机制尚未完全阐明。为了确定多元醇途径在糖尿病引起的视网膜血管功能障碍中的作用，我们研究了醛糖还原酶抑制剂 GP-1447 对糖尿病大鼠 ACh 诱导的视网膜小动脉舒张作用减弱的影响。雄性 Wistar 大鼠用链脲佐菌素（STZ）处理，2 周后进行实验。用含有 5% D-葡萄糖的饮用水处理 STZ 处理的动物，以缩短视网膜血管功能障碍发展的时间。STZ 处理后立即开始用 GP-1447 治疗，并持续整个 2 周的实验期。GP-1447 治疗并未改变 ACh 对视网膜血管反应的减弱，但醛糖还原酶抑制剂完全阻止了糖尿病引起的视网膜变薄、视网膜和晶状体中山梨醇的积累。这些结果表明，尽管多元醇途径在糖尿病大鼠的视网膜形态变化和白内障形成中起着重要作用，但可能有独立于该途径的机制导致了视网膜内皮功能障碍的发生。
