Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Japan.
J Pharmacol Sci. 2010;112(2):176-83. doi: 10.1254/jphs.09219fp.
The concentration of methylglyoxal (MGO), a metabolite of glucose, increases in plasma of type II diabetic patients as well as in tissues of hypertensive rats. We have previously shown that MGO inhibited noradrenaline (NA)-induced smooth muscle contraction in rat aorta. However, the effect of MGO on relaxing responses in isolated blood vessel remains to be clarified. Thus, we examined if MGO affects acetylcholine (ACh)- or sodium nitroprusside (SNP)-induced vasodilation on NA (100 nM)-induced pre-contraction in rat thoracic aorta. Treatment of endothelium-intact aorta with MGO (420 microM, 30 min) did not change ACh (1 nM - 3 microM)-induced endothelium-dependent relaxation. In contrast, treatment of endothelium-denuded aorta with MGO shifted the concentration-response curve for SNP (0.1 - 300 nM) to the left. MGO increased reactive oxygen species (ROS) production in smooth muscle on analysis of protein carbonylation. Anti-oxidant agents such as tempol (10 microM), catalase (5000 U/mL), and nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methylester (100 microM) had no effect on MGO-induced enhancement of SNP-induced relaxation. However, iberiotoxin (100 nM), a large-conductance Ca(2+)-activated K(+) (BK(Ca))-channel inhibitor, significantly prevented the effect. The present study revealed that MGO enhanced SNP-induced relaxation in a ROS-independent manner via in part opening smooth muscle BK(Ca) channels.
甲基乙二醛 (MGO) 是葡萄糖的代谢产物，在 II 型糖尿病患者的血浆中以及高血压大鼠的组织中浓度增加。我们之前已经表明，MGO 抑制了去甲肾上腺素 (NA) 诱导的大鼠主动脉平滑肌收缩。然而，MGO 对分离血管松弛反应的影响仍有待阐明。因此，我们研究了 MGO 是否会影响乙酰胆碱 (ACh) 或硝普钠 (SNP) 诱导的血管舒张对 NA (100 nM) 诱导的大鼠胸主动脉预收缩的作用。用 MGO (420 μM，30 min) 处理完整内皮的主动脉不会改变 ACh (1 nM-3 μM) 诱导的内皮依赖性舒张。相比之下，用 MGO 处理去内皮的主动脉会使 SNP (0.1-300 nM) 的浓度-反应曲线向左移位。在平滑肌蛋白羰基化分析中，MGO 增加了活性氧 (ROS) 的产生。抗氧化剂，如 tempol (10 μM)、过氧化氢酶 (5000 U/mL) 和一氧化氮合酶抑制剂 N(G)-硝基-L-精氨酸甲酯 (100 μM)，对 MGO 诱导的 SNP 诱导的松弛增强没有影响。然而，大电导钙激活钾 (BK(Ca)) 通道抑制剂 Iberiotoxin (100 nM) 显著阻止了这种作用。本研究表明，MGO 通过部分打开平滑肌 BK(Ca) 通道，以 ROS 独立的方式增强 SNP 诱导的松弛。
