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GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure

Nature Medicine volume 19, pages 567–575 (2013)Cite this article

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Abstract

Glucagon-like peptide-1 receptor (GLP-1R) agonists exert antihypertensive actions through incompletely understood mechanisms. Here we demonstrate that cardiac Glp1r expression is localized to cardiac atria and that GLP-1R activation promotes the secretion of atrial natriuretic peptide (ANP) and a reduction of blood pressure. Consistent with an indirect ANP-dependent mechanism for the antihypertensive effects of GLP-1R activation, the GLP-1R agonist liraglutide did not directly increase the amount of cyclic GMP (cGMP) or relax preconstricted aortic rings; however, conditioned medium from liraglutide-treated hearts relaxed aortic rings in an endothelium-independent, GLP-1R–dependent manner. Liraglutide did not induce ANP secretion, vasorelaxation or lower blood pressure in Glp1r−/− or Nppa−/− mice. Cardiomyocyte GLP-1R activation promoted the translocation of the Rap guanine nucleotide exchange factor Epac2 (also known as Rapgef4) to the membrane, whereas Epac2 deficiency eliminated GLP-1R–dependent stimulation of ANP secretion. Plasma ANP concentrations were increased after refeeding in wild-type but not Glp1r−/− mice, and liraglutide increased urine sodium excretion in wild-type but not Nppa−/− mice. These findings define a gut-heart GLP-1R–dependent and ANP–dependent axis that regulates blood pressure.

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Figure 1: Liraglutide reduces blood pressure and promotes aortic relaxation.
Figure 2: Liraglutide stimulates cardiac ANP secretion and elicits aortic vasodilation.
Figure 3: Liraglutide does not stimulate natriuresis or lower blood pressure in hypertensive Nppa−/− mice.
Figure 4: Liraglutide stimulates cardiomyocyte cAMP accumulation, Epac2 translocation and ANP secretion.
Figure 5: Liraglutide stimulates ANP secretion and lowers blood pressure in an Epac2-dependent manner.
Figure 6: ANP is essential for GLP-1–stimulated urinary sodium secretion and vascular smooth muscle relaxation.

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Acknowledgements

We thank G. Kabir for assistance with mouse telemetry and G. Holz (State University of New York Upstate Medical University) for the provision of Epac2 virus constructs. These studies were carried out with support from the Heart and Stroke Foundation of Ontario HSFO NA6997, the Canada Research Chair in Regulatory Peptides, the Banting and Best Diabetes Centre–Novo Nordisk Chair in incretin biology, a grant from Novo Nordisk Inc. to D.J.D., Canadian Institutes of Health Research grant MOP 111159 to J.A.S. and grants to S.S. from the Japan Science and Technology Agency and the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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Authors and Affiliations

  1. Department of Medicine, Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada

    Minsuk Kim, Susan E Quaggin & Daniel J Drucker

  2. Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada

    Mathew J Platt & Jeremy A Simpson

  3. Department of Physiology and Cell Biology, Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan

    Tadao Shibasaki & Susumu Seino

  4. University Health Network and Department of Physiology, University of Toronto, Toronto, Ontario, Canada

    Peter H Backx

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Contributions

M.K., M.J.P. and J.A.S. designed and carried out experiments, analyzed results and wrote the manuscript. M.K. was supported by a postdoctoral fellowship award from the Canadian Diabetes Association. S.S. provided Rapgef4−/− mice, interpreted results and wrote the manuscript. T.S. carried out experiments and reviewed the manuscript. S.E.Q. and P.H.B. helped design experiments and reviewed the manuscript. D.J.D. designed experiments, interpreted results and wrote the manuscript.

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Correspondence to Daniel J Drucker.

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Competing interests

D.J.D. has served as a consultant to Amylin Pharmaceuticals Inc., Eli Lilly Inc., GlaxoSmithKline, Novo Nordisk Inc. and Sanofi Inc.

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Kim, M., Platt, M., Shibasaki, T. et al. GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure. Nat Med 19, 567–575 (2013). https://doi.org/10.1038/nm.3128

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