Nathanson David, Erdogdu Ozlem, Pernow John, Zhang Qimin, Nyström Thomas
Karolinska Institutet, Department of Internal Medicine, South Hospital, Sweden.
Regul Pept. 2009 Oct 9;157(1-3):8-13. doi: 10.1016/j.regpep.2009.07.003. Epub 2009 Jul 10.
Exenatide (synthetic exendin-4) is a stable analogue of glucagon-like peptide 1 (GLP-1) and has recently been approved for clinical use against type 2 diabetes. Exenatide is believed to exert its effects via the GLP-1 receptor with almost the same potency as GLP-1 in terms of lowering blood glucose. Short term exenatide treatment normalizes the altered vascular tone in type 2 diabetic rats, probably due to the reduction in glycemia. The aim of this study was to investigate whether exenatide directly protects against triglyceride-induced endothelial dysfunction in rat femoral arterial rings ex vivo. Short term pre-incubation with Intralipid (0.5 and 2%) was found to dose-dependently induce endothelial dysfunction, in that it elicited a significant reduction in ACh-induced vasorelaxation by 29% and 35%, respectively. Paradoxically, this occurred with a concomitant increase in endothelial nitric oxide synthase (eNOS) activity. No such reduction in vasorelaxation by Intralipid was seen in response to the NO donor sodium nitroprusside (SNP), revealing an endothelium-dependent vascular dysfunction by Intralipid. However, exenatide did not protect against Intralipid-induced endothelial dysfunction. More surprisingly, the maximum vasorelaxation induced by exenatide (without Intralipid was only 3+/-2%, compared to the 23+/-4%, 38+/-4%, 79+/-3% and 97+/-4% relaxations induced by GLP-1, GLP-1 (9-36), ACh and SNP, respectively. This unexpected finding prompted us to ascertain that the exenatide preparation was biologically active, and both exenatide (10(-11) mol/l) and GLP-1 (10(-9) mol/l) significantly increased insulin secretion in pancreatic beta-cells from ob/ob mice in vitro. In conclusion, exenatide could neither confer any acute protective effects against triglyceride-induced endothelial dysfunction nor exert any significant vasorelaxant actions in this model of rat conduit arteries ex vivo.
艾塞那肽（合成的艾塞那肽-4）是胰高血糖素样肽1（GLP-1）的稳定类似物，最近已被批准用于临床治疗2型糖尿病。据信，艾塞那肽通过GLP-1受体发挥作用，在降低血糖方面与GLP-1具有几乎相同的效力。短期艾塞那肽治疗可使2型糖尿病大鼠改变的血管张力恢复正常，这可能是由于血糖降低所致。本研究的目的是调查艾塞那肽是否能在体外对大鼠股动脉环中甘油三酯诱导的内皮功能障碍起到直接保护作用。发现用英脱利匹特（0.5%和2%）进行短期预孵育会剂量依赖性地诱导内皮功能障碍，即它分别使乙酰胆碱诱导的血管舒张显著降低29%和35%。矛盾的是，这伴随着内皮型一氧化氮合酶（eNOS）活性的增加而发生。在对一氧化氮供体硝普钠（SNP）的反应中，未观察到英脱利匹特导致的血管舒张有此类降低，这揭示了英脱利匹特引起的内皮依赖性血管功能障碍。然而，艾塞那肽并不能预防英脱利匹特诱导的内皮功能障碍。更令人惊讶的是，艾塞那肽诱导的最大血管舒张（无英脱利匹特时）仅为3±2%，相比之下，GLP-1、GLP-1（9-36）、乙酰胆碱和SNP诱导的舒张分别为23±4%、38±4%、79±3%和97±4%。这一意外发现促使我们确定艾塞那肽制剂具有生物活性，并且艾塞那肽（10⁻¹¹ mol/l）和GLP-1（10⁻⁹ mol/l）在体外均能显著增加ob/ob小鼠胰腺β细胞中的胰岛素分泌。总之，在这个离体大鼠导管动脉模型中，艾塞那肽既不能对甘油三酯诱导的内皮功能障碍产生任何急性保护作用，也不能发挥任何显著的血管舒张作用。
