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

The peptide hormone GLP-1 has both antidiabetic and antihypertensive effects. Daniel Drucker and his colleagues now show that GLP-1 lowers blood pressure through indirect mechanisms involving the heart: GLP-1 acts on its receptor in atrial cardiomyocytes to stimulate secretion of the peptide hormone ANP, which in turn lowers blood pressure through direct effects on the vasculature and kidney. 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.