Department of Physiology, University College Cork, Cork, Ireland.
J Cardiovasc Pharmacol. 2012 Feb;59(2):182-7. doi: 10.1097/FJC.0b013e31823b4b94.
We tested the hypothesis that metformin produces arterial dilatation indirectly, by directly exposing the endothelial surface, of an occluded test segment of the pig iliac artery in vivo, to test blood containing metformin or excess insulin, with and without the presence of the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester hydrochloride. Such exposure to metformin 1 μg/mL caused the artery to dilate at constant pressure, and this was abolished when NG-nitro-L-arginine methyl ester hydrochloride was coadministered with metformin. The onset of dilatation occurred approximately 4 minutes after the commencement of endothelial exposure to metformin; this contrasts with the approximate 10 minutes required for a similar response to luminal hyperinsulinemia. After the release of flow occlusion, the subsequent flow-mediated dilatation was slightly but significantly enhanced compared with control for metformin; the effect of insulin on flow-mediated dilatation was not statistically significant. The hypothesis was disproved, as we have shown that insulin and metformin, like insulin, directly stimulate NO production by endothelium of a conduit artery; this function may be of value in delaying the atherothrombotic process. The time taken for the commencement of NO production is shorter for metformin than for insulin; the clinical relevance of this finding is unclear.
我们测试了一个假设，即二甲双胍通过直接暴露于体内猪髂动脉闭塞测试段的内皮表面，使含有二甲双胍或过量胰岛素的测试血液间接产生动脉扩张，并在存在或不存在一氧化氮（NO）合酶抑制剂 NG-硝基-L-精氨酸甲酯盐酸盐的情况下进行测试。这种暴露于 1μg/mL 的二甲双胍会导致动脉在恒定压力下扩张，而当与二甲双胍一起给予 NG-硝基-L-精氨酸甲酯盐酸盐时，这种扩张就会被消除。扩张的开始发生在内皮暴露于二甲双胍后大约 4 分钟；这与对腔内线粒体高胰岛素血症的类似反应所需的大约 10 分钟形成对比。在释放血流闭塞后，与对照相比，随后的血流介导的扩张略有但显著增强，而胰岛素对血流介导的扩张的影响在统计学上不显著。该假设被否定了，因为我们已经表明，胰岛素和二甲双胍与胰岛素一样，直接刺激管腔动脉内皮细胞的 NO 产生；这种功能可能有助于延缓动脉粥样血栓形成过程。NO 产生的起始时间对于二甲双胍来说比胰岛素要短；这一发现的临床意义尚不清楚。
