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

Minsuk Kim, Mathew J. Platt, Tadao Shibasaki, Susan E. Quaggin, Peter H. Backx, Susumu Seino, Jeremy A. Simpson, Daniel J. Drucker*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

378 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)567-575
Number of pages9
JournalNature Medicine
Issue number5
StatePublished - May 2013

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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