Endothelial dysfunction induced by triglycerides is not restored by exenatide in rat conduit arteries ex vivo

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / metabolism
  • Exenatide
  • Femoral Artery / drug effects*
  • Femoral Artery / metabolism
  • In Vitro Techniques
  • Male
  • Peptides / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Triglycerides / pharmacology*
  • Venoms / pharmacology


  • Peptides
  • Triglycerides
  • Venoms
  • Exenatide