期刊
REGULATORY PEPTIDES
卷 157, 期 1-3, 页码 8-13出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.regpep.2009.07.003
关键词
Endothelial function; eNOS; Exenatide; GLP-1; Intralipid
资金
- Swedish Society for Medical Research
- Swedish Society of Medicine
- European Foundation for the Study of Diabetes
- Olle Engkvist Byggmastare Foundation
- Ake Wibergs Foundation
- Loo and Hans Foundation
- Tore Nilsson Foundation
- Fredrik and Ingrid Thurings Foundation
- Merck Sharp Dohme
- Swedish Research Council [10857, 72X-12550, 72X-14507, 72P-14787]
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 (R) (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 (R) was seen in response to the NO donor sodium nitroprusside (SNP), revealing an endothelium-dependent vascular dysfunction by Intralipid (R). However, exenatide did not protect against Intralipid (R)-induced endothelial dysfunction. More surprisingly, the maximum vasorelaxation induced by exenatide (without Intralipid (R)) 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/I) and GLP-1 (10(-9) mol/I) 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. (c) 2009 Elsevier B.V. All rights reserved.
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