Glucagon-like peptide-1 relaxes rat conduit arteries via an endothelium-independent mechanism
Introduction
Glucagon-like peptide-1 (GLP-1) has attained much interest as an emerging new drug in the treatment of type 2 diabetes mellitus [1], [2]. GLP-1 is secreted by enteroendocrine l-cells in the small intestine in response to ingestion of food and augments the insulinotropic effect of nutrients through an incretin effect [3], [4], [5], [6]. GLP-1 stimulates insulin secretion and inhibits glucagon secretion which lowers plasma glucose levels in type 2 diabetes patients. Another important effect of GLP-1 on glycemia is through inhibiting small bowel motility, an effect that is nitric oxide (NO)-dependent in the fasted but not fed state [7]. Additional effects of GLP-1, apart from glycemic influence, have been reported and high-affinity receptors for GLP-1 are present in various tissues [8]. In the cardiovascular system, GLP-1 has been shown to increase systolic blood pressure and heart rate in rodents [9], [10], [11], to cause vasorelaxation in the pulmonary circulation in rats [12], [13] and to improve severe left ventricular heart failure in human suffering from a myocardial infarction [14]. Recently, we demonstrated that GLP-1 ameliorates endothelial dysfunction in type 2 diabetes mellitus patients with established coronary heart disease, suggesting a novel and important cardioprotective effect for GLP-1 (unpublished data). One salient feature in type 2 diabetes mellitus patients is endothelial dysfunction which closely correlates to cardiovascular death [15]. Therefore, any positive influence of GLP-1 on endothelial function may prove useful in preventing premature cardiovascular disease in diabetic patients. However, the involvement of the endothelium for the effect of GLP-1 in systemic arteries remains to be determined.
In the present study, we wanted to characterize the possible direct effects of GLP-1 in the vasculature, thereby gaining mechanistic insights into the salutary actions of GLP-1 on endothelial function. Therefore, the aim of this study was to examine whether GLP-1 has direct vascular effects on conduit vessels and to investigate the mechanism underlying an effect including involvement of endothelium-derived NO.
Section snippets
Materials and methods
This study was approved by the regional ethics committee for animal research and conforms to the Guide for the Care and Use of Laboratory Animals published by the US National Institute of Health (NIH publication No. 85-23, revised 1985).
Results
All vessels tested responded well to ACh and the NO donor SNP in a dose-dependent manner, demonstrating a valid working model for studies of endothelium-dependent and -independent relaxation effects (Fig. 1a and b). Furthermore, the NO synthase inhibitor l-NNA attenuated the relaxations induced by ACh, further demonstrating the involvement of NO in this action (Fig. 1a).
GLP-1, applied during basal tension, was without any discernable contractile effect on the femoral artery rings (data not
Discussion
We show in the present study that GLP-1 potently and dose-dependently relaxes rat conduit arteries. Even if the magnitude of the is relaxant action was threefold less than that of for ACh, GLP-1 was very potent with a significant relaxation already at 10−11 mol/l, although at this low concentration the vasorelaxant action was modest (5 %). The specific GLP-1 receptor antagonist exendin(9–39) completely blocked the relaxant action of GLP-1, indicating the specificity of the GLP-1 relaxant
Acknowledgments
We dedicate this paper to the memory of Mark K. Gutniak, M.D., Ph.D., a pioneer in GLP-1 research and a great inspirator and friend. Financial support was received from the Swedish Research Council (# 10857, 72X-12550, 72X-14507 and 72P-14787), the European Foundation for the Study of Diabetes, the Nutricia Research Foundation, the Swedish Society of Medicine, Stiftelsen Serafimerlasarettet, the Sigurd and Elsa Golje Memorial Foundation, Svenska Försäkringsföreningen, Berth von Kantzow's
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